TRANSLATIONAL PHYSIOLOGYLoop diuretics: from the Na-K-2Cl transporter to clinic - 《American Journal of Physiology》美国生理学杂志干细胞之家



免疫细胞治疗专区	欢迎关注干细胞微信公众号

12 3 4 5 6 7 8 9 10 ... 26 下一页

返回列表

查看: 578289\|回复: 252	go TRANSLATIONAL PHYSIOLOGYLoop diuretics: from the Na-K-2Cl transporter to clinic [复制链接]

轻羽

新手上路

Rank: 1

积分: 0
威望: 0
包包: 0

楼主

发表于 2009-4-21 13:25 |只看该作者 |倒序浏览 |打印

作者：Sudha S.Shankar and D. CraigBrater作者单位：Division of Clinical Pharmacology, Department of Medicine,Indiana University School of Medicine, Indianapolis, Indiana46202-5124
   & }" z+ r5 F! t: }$ N- _


                     ; F4 u; s: u& O; C

         # }9 i* g5 r' a7 j. s7 `* [5 Q
         - [# n, W7 k+ o/ T  }# ]7 J
         ' A2 S) I2 A# T; O5 v8 E! u) T; d9 N: A
                  1 K  K* D$ T0 m. `+ B- ?4 W4 X
      - J9 q& m9 j( J, i


      【摘要】4 u+ o! @" L. s) g% F7 n0 g7 E9 z- B
   The diuretic response to loop diureticsin various disease states has consistently been found to be subnormal.One of the key determinants of the degree of diuretic response is thefunctional integrity of the sodium-potassium-chloride transporter inthe loop of Henle. Studies in animal models suggest thatexpression/activity of the transporter may be affected by factors suchas altered natural splicing events of NKCC2 (the gene encoding for therenal transporter), renal prostanoids, vasopressin, and otherautacoids. We have reviewed the pharmacokinetics and pharmacodynamicsof loop diuretics in health and in edematous disorders for which theyare used. On the basis of evidence reviewed in this paper, we proposethat 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 alteredexpression/activity could serve as important therapeutic targets foralternative diuretic regimens in these conditions.
      【关键词】 edematous disorders furosemide
   INTRODUCTION* |8 s" n! P* h2 R. F

OPTIMAL THERAPEUTIC USE of loopdiuretics requires an understanding of their basic pharmacology and howthat translates to clinical pharmacology. As will be emphasized, thetwo complement one another in that discoveries in the domain ofpharmacology lead to testable hypotheses as to clinical application.Similarly, clinical observations logically lead to studies bestperformed at the bench. For example, studies of the pharmacodynamics of loop diuretics in patients with heart failure consistently show thatthere is a subnormal response to amounts of diuretic reaching the siteof action. There are several potential explanations for thisobservation, each of which dictates a different therapeutic strategy.The possible explanations would be difficult to dissect throughclinical studies. For example, one possible explanation is alteredexpression or activity of the Na-K-2Cl transporter at the loop ofHenle. It goes without saying that one could never measure suchexpression in a clinical study. In contrast, one can imagine addressingsuch a question in an appropriate animal model. If such a model showedthat there was no difference in expression of the transporter, thenalternative mechanisms should be explored. If, on the other hand, therewere substantial changes in expression or activity of the transporterin heart failure, one would then need to ponder appropriate therapeuticstrategies and test them in controlled clinical trials.5 l5 A5 I# V3 e7 ~( `
8 U5 H" g2 g+ j8 }
PHARMACOLOGY OF LOOP DIURETICS# m+ i' Y! W6 B; E8 ?  f8 U

Loop diuretics act principally by blocking the luminal Na-K-2Cltransporter in the thick ascending limb of the loop of Henle; in otherwords, this transporter is the receptor for loop diuretics ( 15, 31, 40, 42, 64, 69, 78, 80 ). This transporter has been clonedand sequenced, and its expression has been mapped to different segmentsof the nephron as well as other tissues ( 66, 69, 70 ). Itis a protein with a core molecular mass of 121 kDa, having 12 putativemembrane-spanning domains ( 42, 70 ). Loop diuretics bind toportions 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 type1 bumetanide-sensitive Na-Cl cotransporter (BSC-1)/NKCC2 gene onchromosome 2, and rat BSC-1 protein is localized to the apical membraneof epithelial cells in both medullary and cortical segments of thethick ascending limb of the loop of Henle ( 66, 69, 70 ).Several investigators have shown that it is expressed throughout thethick ascending limb of the loop of Henle, including the macula densa( 66, 69, 70 ). Interestingly, nitric oxide (NO) synthase iscoexpressed in the macula densa, suggesting that the Na-K-2Cltransporter may serve as the sensor of luminal chloride delivery to themacula densa and that NO is a mediator or modulator of subsequenteffects in concert with or through locally synthesized prostanoids( 77 ). Expression of Na-K-2Cl is at the luminal membranebut also in cytoplasmic vesicles, suggesting a reservoir oftransporters for insertion into the membrane ( 66, 69 ). Inturn, these vesicles are more predominant in smooth- thanrough-surfaced thick ascending limb cells; the former are mainly in themedullary portion of the thick limb. Thus the transporter that servesas the receptor for loop diuretics is expressed at the apical surfaceof both the medullary and the cortical sections of the thick ascending limb of the loop of Henle, including the macula densa. It resides incytoplasmic vesicles, offering a mechanism for altered activity of thetransporter by way of increasing or decreasing the numbers oftransporters inserted into the membrane.4 G/ e" k+ ?8 N6 k  f2 D1 _. B7 d

In addition to the renal Na-K-2Cl transporter, there is a ubiquitousNa-K-2Cl transporter encoded by BSC-2/NKCC1 that is expressed in manytissues. Loop diuretics have little if any effect on this lattertransporter in vivo. In contrast, ex vivo they inhibit its activity. Invivo selectivity derives from three factors. First, the renal Na-K-2Cltransporter has about a fourfold greater affinity for bumetanide andpresumably other loop diuetics ( 41, 49 ). Second, there arelikely differences in access of the loop diuretic to the site oftransporter expression. All loop diuretics are highly bound to serumalbumin, and this binding restricts their access to many tissues, asmight physicochemical properties such as their negative charge and poorlipid solubility. Access to renal Na-K-2Cl receptors occurs via activesecretion. One must presume that such an avenue of access is notpresent at sites of expression of the ubiquitous Na-K-2Cl transporter.Third, once a loop diuretic is secreted into the proximal tubule, as itflows to its site of activity at the thick ascending limb of the loop of Henle, it becomes more concentrated.' D+ Z2 t* C/ v# f' e3 ~* X1 A- r3 I
% t) k1 h9 z& @$ {* r
Studies in animal models have explored ways in which expression of theNa-K-2Cl transporter might be altered (Fig. 1 ). It is now abundantly clear thatvasopressin itself, either exogenously or endogenously, or its analogsincrease expression of the transporter ( 24, 55 ). It isimportant to note that vasopressin might also cause increased insertionof transporters over and above increasing their expression. Studieswith knockout mice (G s knockout) indicate that thiseffect of vasopressin is through G s, presumably to increase cAMP, which then increases transporter expression via a cAMPregulatory element of the BSC-1/NKCC2 gene ( 24 ) (Fig. 1 ).The net effect would be an increase in solute reabsorption at the thicklimb, contributing to sodium retention and also increasing the drivingforce for water reabsorption (Fig. 1 ). It is intriguing to note thatvasopressin also causes increased aquaporin expression and insertion,thereby increasing the channels available for water reabsorption( 2, 59, 97, 103 ). That effect, coupled with the increasedosmotic driving force for water reabsorption noted above and withnonosmotically mediated increases in vasopressin in edematous disorders( 84, 85 ), can readily account for the inability to excretefree water and the hyponatremia that is a characteristic of theseclinical conditions (Fig. 2 ). These data suggest that the vasopressin-mediated increase in expression of theNa-K-2Cl transporter amplifies the defect in water excretion inedematous 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 anoverly simplistic explanation for an altered diuretic response.) ^) \8 r4 P6 w( B; Q/ T0 e
  p. g7 a3 m* E& \, m: U2 K
Fig. 1. Regulation of expression of the Na-K-2Cl transporter at the thickascending limb of the loop of Henle and the macula densa./ O6 X+ s: B4 R8 c( [& {
* ]* z" r- X1 R- `. Y
Fig. 2. Potential multiple influences of vasopressin in causinghyponatremia in the edematous disorders.

The expression of the Na-K-2Cl transporter may also be influenced byalternate natural splicing events of the BSC-1/NKCC2 gene, with variousdegrees of expression of the different exons ( 66 ). Inturn, this alternative splicing results in different transportercapacities ( 36 ). Disease-induced changes in splicing ordistribution of splice variants could conceivably contribute to analtered cumulative response to a loop diuretic.
9 T8 |& ^) e2 m( z$ O
The expression of the Na-K-2Cl transporter is also influenced by renalprostanoids, wherein PGE 2 decreases its expression ( 29 ) (Fig. 1 ). PGE 2 activates the EP3receptor, causing decreases in cAMP via G i; through thecAMP regulatory element, expression of the transporter decreases. Suchan effect would decrease the driving force for water reabsorption andthereby diminish the hydrosmotic response to vasopressin, a well-knowneffect of PGE 2 ( 44 ). This role ofPGE 2 could also explain the effect of nonsteroidal anti-inflammatory drugs in causing sodium and water retention, aneffect that has been shown in clinical studies to occur anatomically atthe thick ascending limb ( 51 ). It is interesting to note that administration of vasopressin and also edematous disorders arecharacterized by increases in renal prostanoids. Presumably, thisrepresents a negative-feedback loop to ameliorate the sodium- andwater-retentive effects of the edematous disorders. Thispathophysiology also likely accounts for the sometimesdevastating clinical effects of acute renal failure ( 16, 20, 83 ) or decompensation of heart failure ( 45, 65 )that can occur when such patients are administered nonsteroidalanti-inflammatory drugs.
' b6 ^9 y! s3 n: x" ~: z
Vasopressin and other autacoids could also affect activity of thetransporter in addition to its expression. Extensive studies have beenperformed with NKCC1 showing numerous fashions by which activity couldbe modified, including phosphorylation by any of a number of kinases( 42 ). Presumably, the same potential applies to the renalNa-K-2Cl transporter.1 Q  `; E; E+ w7 `
, c+ z; s" ~' h, N1 F) _
From the foregoing, one would predict that increased expression of theNa-K-2Cl transporter occurs in the common clinical conditions treatedwith loop diuretics. In turn, might increased expression account, atleast in part, for the diminished response to loop diuretics thatoccurs in the edematous disorders? This mechanism is likely overlysimplistic. As will be discussed, the response to loop diuretics in theedematous disorders is characterized by a decrease in response to amaximally effective dose. If vasopressin simply caused moretransporters to be present in the thick ascending limb of the loop ofHenle, one would expect that administration of a dose of loop diureticsufficient to block all of them would result in an increased maximalresponse. Thus one must postulate a more complicated scenario ofaltered activity and/or of events occurring at other segments of thenephron that obviate this manifestation of increased expression. Forexample, increased proximal and/or distal reabsorption of sodium couldcontribute. The answers to these questions are open and not onlyrepresent scientific opportunities for the future but are alsoimportant for the design of future therapeutic diuretic regimens.Importantly, the anticipated availability of vasopressin antagonistsfor clinical use will allow logical exploration of these differentpossibilities in parallel with studies at the bench that unravelthis undoubtedly complicated pathophysiology.
% ]  D6 D6 S/ Y- a' N) B, G* q
PHARMACOKINETCS OF LOOP DIURETICS5 ]% y/ Z$ w3 o" `( W
, N5 r8 g0 n! z* o9 F( |
Loop diuretics reach the Na-K-2Cl transporters that are insertedinto the luminal membrane by being actively secreted from the bloodinto the urine at the proximal tubule ( 71 ). High albumin 95%) minimizes glomerular filtration. Binding to albumin traps the diuretic in the plasma and transports it to organic acidsecretory sites at the proximal tubule. These secretory pumps have suchavidity for the loop diuretic that the diuretic is in effect"stripped" from the albumin and transported across the cell intothe lumen, where it gains access to the Na-K-2Cl transporters that aredownstream of the secretory sites.
. `$ U# w# B6 b  g+ K
Fifty percent of a dose of furosemide is excreted as active, unchangeddrug into the urine ( 7, 10 ); the remainder is conjugatedto glucuronic acid in the kidney itself ( 76 ). In patientswith renal insufficiency, the plasma half-life of furosemide isprolonged because both urinary excretion and renal conjugation aredecreased ( 7, 8, 10, 21, 47, 89 ) (Table 1 ). Bumetanide and torsemide havesubstantial metabolism (50 and 80%, respectively), but with these loopdiuretics metabolism is hepatic rather than renal ( 11, 14, 22, 46 ). Therefore, their half-lives are not prolonged in patientswith renal insufficiency, because the liver provides an alternativeroute for elimination (Table 1 ). Just as occurs with furosemide, withthese two loop diuretics renal disease impairs delivery into thetubular fluid. In patients with hepatic disease, the plasma half-livesof bumetanide and torsemide are prolonged, allowing more to reach thetubular fluid, an effect that can paradoxically enhance response( 10, 86 ) (Table 1 ).

Table 1. Pharmacokinetics of loop diuretics
' F& g+ N# H+ K2 E* |
Ethacrynic acid is another loop diuretic; there are no data concerningits pharmacokinetics. Its ototoxic effects have seemed to be greaterthan that of other loop diuretics, causing its use to be relegated topatients who have allergic reactions to other loop diuretics. It willnot be discussed.
& [6 u4 d/ ^3 n$ h4 G% t
Other pharmacokinetic features of diuretics that are clinicallyimportant are bioavailability and half-life. On average, half a dose offurosemide is absorbed but with a large range (10-100%) ( 10, 68 ). This variability makes it difficult to predicthow much furosemide will be absorbed in an individual patient.Clinically, this means that one may need to explore a wide range ofdoses in an individual patient to determine the appropriate oraldose. 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 ourlaboratory reports fewer hospitalizations and better quality of life inpatients with heart failure treated with a completely absorbed loopdiuretic as represented by torsemide compared with furosemide( 67 ). Edematous disorders do not cause malabsorption ofloop diuretics ( 6, 13, 18, 34, 86, 91, 94, 95 ). Absorptionis slowed, particularly in patients with decompensated heart failure( 95 ), but the total amount absorbed is the same as inhealthy individuals. The clinical implications of slowed absorption are unclear.

The plasma half-lives of loop diuretics range from ~1 h forbumetanide to 3-4 h for torsemide; that for furosemide isintermediate ( 10 ). Neither a truly long-acting loopdiuretic nor a sustained-release preparation is available. Thetraditional dosing intervals of all loop diuretics exceed the durationof time when effective amounts of drug are at the site of action. Thismeans that at the end of the dosing interval there is considerable timeduring which there are inadequate amounts of diuretic at the site of action. During this time, the nephron avidly reabsorbs sodium, causingso-called "rebound" sodium retention or "braking"( 102 ). This sodium retention can be of sufficient extentas to nullify the prior natriuresis. This is particularly the case ifthe response is modest, if the time of no drug effect is long (forexample, a short half-life coupled with a long dosing interval), and/or if dietary sodium is high relative to response. Dietary intake isparticularly a problem if salt indiscretion occurs at the end of adosing interval wherein most of the sodium is retained( 28 ). As a consequence, it may be wise for patients totake their doses of loop diuretics at times that correspond to sodium ingestion.
* K$ i7 g) r, Y
In summary, excepting the infrequently used ethacrynic acid, thepharmacokinetic characteristics of loop diuretics are well defined.These data allow logical choices, depending on the needs of individualpatients, of which loop diuretic to use. Choice of dose and thefrequency of dosing are driven not only by these pharmacokineticcharacteristics but also by the pharmacodynamics of loop diuretics inthe different clinical conditions in which they are used.* U4 e* B5 \* K' y3 S

PHARMACODYNAMICS OF LOOP DIURETICS
& w4 Y% ]+ t6 C' e  M* q% I) n4 k
The urinary excretion rate of a loop diuretic has been shown to bea reliable measure of amounts of diuretic reaching the site of actionand can be used as a surrogate for concentration in a typicalconcentration-response analysis of diuretic action ( 10, 19 ). Urinary concentration has not proven to be a useful measurebecause the concentration of diuretic in the final urine does notrepresent that at the site of action. Simplistically, the more diureticreaching its site of action, the greater the response so that the netresult is that diuretic concentration in the final urine is constant.Therein, the diuretic excretion rate is a better reflection of theamount of diuretic that is able to interact with the Na-K-2Cltransporter. The relationship between diuretic delivery and response,measured as urinary sodium excretion, chloride excretion, or fractionalexcretion of either, is characterized by a sigmoidally shaped curve, aso-called sigmoid E max model ( 9 ). Thisrelationship holds for all loop diuretics, although the position ofeach on the x -axis differs, because of differences inpotency; namely, the excretion rate that causes a half-maximal responsebeing 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 amountsto a fractional excretion rate of sodium of ~20-25% in ahealthy volunteer. This value is important, because it implies that amaximally effective dose of a loop diuretic is capable of completelyblocking sodium reabsorption in the thick limb. In turn, once amaximally effective dose is administered, the only way to increaseresponse is to block other segments of the nephron.* f- [+ F$ Y- X  t# r# m
5 o2 v+ s4 b8 Q- }4 d4 Q, t
Several features of the sigmoidal shape of the pharmacodynamicrelationship are important clinically. First, there is a threshold quantity of drug that must be achieved at the active site to elicit aresponse. Because of individual differences in sensitivity of thenephron and individual differences in pharmacokinetic characteristics, the dose that attains this threshold differs among patients.Clinically, this means patients should have doses tailored to theirindividual needs and that physicians should realize that a process ofdose titration needs to occur in each patient. As noted above, the second feature of this pharmacodynamic relationship is that a maximalresponse can be identified, allowing definition of the ceiling dose ofa diuretic, namely, the smallest dose of a diuretic that elicits amaximal response and therefore the dose that should not be exceeded.
/ H% |) f& K, H: u; c# K# q& [
In healthy volunteers, an intravenous dose of 40 mg of furosemide, 20 mg of torsemide, or 1 mg of bumetanide causes a maximal response, whichis the excretion of 200-250 meq of sodium in a urine volume of3-4 liters over a time interval of 3-4 h ( 10 ). In other words, loop diuretics cause excretion of urine with a sodiumcontent resembling 0.5 normal saline. Knowing this fact can be helpfulto clinicians in predicting the amount of sodium excreted based onsimple measures of urine volume.& _$ u. g! h; c" Q( j0 W/ t) h5 a
  `+ E8 F; ^6 n, s. K( y
Tolerance to Loop Diuretics

There are two forms of tolerance to loop diuretics. Acutetolerance, or braking, refers to a decrease in response to a loop diuretic early in its use, in fact, within the duration of effect ofthe first dose. This type of tolerance can be prevented by restoringdiuretic-induced loss of volume, implying that volume loss per se isthe 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 systemactivation, or both. However, neither converting enzyme inhibition noradrenergic blockade, separately and together, consistently prevents it( 54, 75, 101 ). Thus other as yet unidentified mechanismsmust also be involved. Acute tolerance is an important factor in thetiming of doses of a loop diuretic and in the frequency of dosing.Because of the short half-lives of loop diuretics relative to theirusual dosing interval, there can be a substantial period of time at theend of a dosing interval where amounts of diuretic are below thethreshold needed to cause an effect. During this time, when homeostaticmechanisms have been triggered, avid sodium retention can occur. If thepatient ingests sodium during these times, most or all of it will beretained, potentially obviating the diuretic effect ( 28 ).Several strategies can be used to counter this effect, including morefrequent dosing, decreasing overall sodium intake, and/or coordinatingdiuretic and food ingestion so that the latter occurs at a time whensufficient amounts of diuretic are at the site of action, as, forexample, ingestion within 2 h of administration of the diuretic( 28 ). This problem could be most readily overcome byhaving a truly long-acting loop diuretic or a sustained-releasepreparation of one of them. Unfortunately, the chemical characteristicsof all available loop diuretics have withstood substantial efforts to formulate such a product." e0 R1 C& @+ o7 u) c+ K) `. F7 m, T
7 a$ c; }: o; @& G# b1 P
The second type of loop diuretic tolerance occurs with chronicadministration. 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 andconnecting duct segments of the nephron, with concomitant increases inreabsorption of sodium ( 25, 50, 60, 63, 88 ). Therein,sodium rejected from the loop of Henle is then reclaimed at thesesites, decreasing overall diuresis. Thiazide diuretics block thenephron sites at which hypertrophy occurs, accounting for thesynergistic response to the combination of a thiazide and a loopdiuretic ( 26, 27, 72, 87 ). This phenomenon reinforces thelogic of using combinations of loop and thiazide diuretics in patientswho 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 toone-tenth as much loop diuretic into the tubular fluid as a healthyvolunteer ( 7, 10 ). Thus a large dose must be given toattain an effective amount of diuretic in the tubule (Table 2 ). When sufficient doses areadministered to attain effective amounts of the loop diuretic in theurine, the relationship between excretion rate of diuretic and responsemeasured as fractional excretion of sodium is the same in patients withrenal insufficiency as in healthy volunteers ( 93, 99 ).Thus remnant nephrons in patients with renal insufficiency retain theirresponsiveness. That having been said, a response in terms of totalurinary sodium excretion never reaches that for a healthy volunteerbecause the decrease in renal function limits filtered sodium (Fig. 3 ). Clinically, this means that amaximally effective dose of a loop diuretic in a patient with renalinsufficiency may not result in the needed overall diuresis and thatother measures including frequent dosing, combining diuretics, and/orrestricting dietary sodium may also need to be employed.

Table 2. Therapeutic strategies for use of loop diuretics' Z# Y. G' ?0 C/ H8 U! _

Fig. 3. Decrease in overall sodium excretion from a maximallyeffective dose of a loop diuretic in renal insufficiency due todecreased filtered load. A : fractional excretion of sodium(FE Na ). B : overall sodium excretion rate.) d+ [& n% W9 g9 Y7 g! _
3 ^; p( Q! \# g, a
As noted above, the sigmoidal nature of the pharmacodynamicrelationship allows definition of a dose of loop diuretic that causes amaximal response. Because this relationship is maintained in patientswith renal insufficiency, one can determine the largest dose that needsto be administered in such patients. Clinical studies have shown that amaximal natriuretic response occurs with intravenous bolus doses of160-200 mg of furosemide, 6-8 mg of bumetanide, and80-100 mg of torsemide ( 81, 99 ). Nothing but the riskof toxicity is gained by larger single doses. Single intravenous bolusdoses of this magnitude can occasionally cause transient tinnitus( 33, 35 ). Such effects can likely be minimized byadministering the dose by infusion over 20-30 min, although thishas never been systematically studied.1 C+ A' R+ z/ {2 C/ r' n- {) T% b

As discussed previously, one aspect of the short half-lives of all theloop diuretics is the duration of time at the end of the dosinginterval where avid sodium retention can occur. In the appropriateclinical setting, a continuous intravenous infusion can be used tomaintain effective amounts of the diuretic at the site of action at alltimes. This strategy results in a small (20-30%) but sometimesclinically important increase in overall response ( 82 ).This approach can be used in all edematous disorders ( 23, 61, 62, 92 ). If one intends to use a continuous infusion of a loopdiuretic, a loading dose must first be given to decrease the timeneeded to attain adequate amounts of diuretic at the site of action(Table 3 ); otherwise, 6-20 h arerequired to reach steady state, depending on the diuretic used and thepatient's renal and/or hepatic functional status. The rate of thecontinuous infusion is determined as follows = serum concentration ×6 [& S  Q/ w5 t% e/ x2 k5 a

The desired urinary excretion rate is known from clinical studiesin patients with renal insufficiency, where the pharmacodynamic relationship has been defined; renal diuretic clearance and serum diuretic clearance are known from prior pharmacokinetic studies in suchpatients. The former allows calculation of the needed serumconcentration. This value plus serum clearance then allows calculationof the continuous infusion rate (Table 3 ). Such infusion rates havebeen tested and validated in appropriate patient groups ( 23, 61, 62, 82, 92 ).
! ]$ [5 @( Y( \/ U. S
Table 3. Doses for continuous intravenous infusion of loop diuretics9 v1 E) l8 U' `! e) s( w( ?! W1 {# W, H

In summary, a patient who needs a loop diuretic and who has renalinsufficiency should be given increasing doses of a loop diuretic untilan effective dose is found or the ceiling dose relative to theindividual patient's renal function is reached (Table 2 ). When aneffective dose is found, its dosing frequency is based on thepatient's response and ability to restrict sodium intake as well asthe duration of action of the loop diuretic chosen.5 S% K5 V& Z9 x  ]: i5 k

Nephrotic syndrome. Several changes occur in nephrotic syndrome that can affect thepharmacokinetics of loop diuretics. Two factors can affect delivery ofthe diuretic to its site of action, namely, inadequate secretion fromblood to lumen of the nephron or alternatively binding of the loopdiuretic to albumin in the tubular lumen. In terms of the former,studies in analbuminemic rats show that hypoalbuminemia may result ininsufficient delivery of drug into the tubular fluid ( 48 ).As noted previously, the high degree of binding of loop diuretics toplasma albumin traps the diuretic in the vascular space and carries itto secretory sites in the kidney. In the absence of circulatingalbumin, loop diuretics are no longer restricted to the plasma (asreflected by a 10-fold increase in volume of distribution in theanalbuminemic rat) and reach the secretory sites to a substantiallydiminished degree; therefore, less diuretic is secreted into the lumen,resulting in inadequate natriuresis ( 48 ). In analbuminemicrats, administration of a mixture of albumin and a loop diureticrestores bound diuretic to the animal. This results in a normalizationof the volume of distribution and increased delivery of diuretic intothe urine, restoring the response ( 48 ). That thismechanism might be operative in humans was suggested by a report thatadministration of 30 mg of furosemide mixed ex vivo with 25 g ofalbumin enhanced diuresis in several patients with nephrotic syndrome( 48 ).
( M0 M5 Z4 R+ C  t9 {
It is important to emphasize that this therapeutic strategy is aimed atincreasing amounts of diuretic in the urine in hypoalbuminemic patients; it is not a strategy to alter the pharmacodynamics of theloop diuretic. Therein, it should be noted that pharmacokinetic studiesin patients with both nephrotic syndrome ( 53, 79 ) andcirrhosis ( 32, 52, 90, 96, 98 ) show that normal excretionrates of furosemide reach the tubular fluid unless the patient also hasrenal insufficiency. These observations therefore raise the question ofwhy a strategy of administering albumin should even be considered.Several recent studies, including one from our laboratory, haveassessed the efficacy of albumin-furosemide mixtures in hypoalbuminemicpatients and shown no increase in response over the loop diuretic alone( 3, 17, 30 ). A caveat is that most of the patients in thereported studies had serum albumin concentrations of 2 g/100 mlor higher, suggesting that this level of circulating albumin issufficient to deliver adequate excretion rates of diuretic. As such,there are sufficient data to reject use of loop diuretic plus albuminmixtures in patients with serum albumin concentrations above thisvalue. In patients with more severe hypoalbuminemia, there are noclinical data. Consequently, it would seem reasonable that such astrategy can be considered but only after adequate doses of loopdiuretic alone have been attempted and with the understanding that thistherapy is experimental.; B9 ]" M2 E( Q! ?  R
! g" G3 c- P$ |( [" n2 H; w
As noted above, loop diuretics could theoretically bind to filteredalbumin, rendering them inactive. In this scenario, although adequateamounts of total diuretic reach the site of action, the amount ofunbound, active diuretic is insufficient to reach the threshold forresponse ( 37, 38, 56, 57 ). In animal models where thetubule is made "nephrotic" by including albumin in the tubularperfusate, the response is subnormal, and it can be restored bydisplacing the diuretic from urinary albumin ( 56, 57 ). Itappears that nephrotic range proteinuria is able to bind one-half totwo-thirds of the diuretic that reaches the tubular fluid. Consequently, diuretic doses two to three times greater than normal areneeded to deliver adequate amounts of unbound, active drug to the siteof action (Table 2 ). Another logical strategy to enhance the responsein patients with albuminuria would be to administer another drug thatcould displace the loop diuretic from binding, thereby restoringamounts of unbound, pharmacologically active drug. A clinical studyfrom our laboratory has tested this hypothesis and found that nobenefit accrued, suggesting that other factors are more important indetermining overall response in nephrotic patients ( 1 ).
" R# l  ]9 @9 m. E3 G* {- Q
Because the delivery of diuretic into the urine is satisfactory andbecause urinary albumin binding is of minor quantitative importance, itis clear that pharmacodynamic factors are the major cause of adecreased response to loop diuretics in patients with nephroticsyndrome ( 53, 79 ) (Table 2 ). The mechanism of this alteredresponse is unknown. Increased proximal and/or distal reabsorption ofsodium may contribute ( 10 ). Interestingly, in a rodentmodel of nephrotic syndrome, a component of the changed response occurswithin the loop of Henle itself ( 58 ). Might increasedexpression or altered activity of the Na-K-2Cl transporter occur andhow might it influence response? Studies of such expression andactivity in animal models would be interesting, as would assessment ofthe effect of vasopressin antagonists on response to a loop diuretic.9 }- X: |" J6 b/ B6 b, l
2 x7 Q( ?& {  v# X
In summary, patients with nephrotic syndrome have at least apharmacokinetic plus a pharmacodynamic mechanism for decreased loopdiuretic response (Table 2 ). Overcoming binding of diuretic to urinaryalbumin requires a sufficient dose to attain normal excretion rates ofunbound diuretic in the urine. This amount defines the ceiling doselisted in Table 2. The diminished pharmacodynamics of response mandatesfrequent dosing and often addition of a thiazide diuretic. If thesestrategies fail and the patient is severely hypoalbuminemic, a mixtureof loop diuretic and albumin can be attempted. We recommend mixing aceiling dose with 25 g of albumin. This strategy should beconducted in a fashion such that response can be closely monitored toallow a definitive conclusion as to whether the combination waseffective and should or should not be continued.
" z8 i& W$ _. G* H# I3 g
Cirrhosis. Patients with cirrhosis receive loop diuretics only if their disease isso severe that spironolactone and thiazides are not effective; eventhen, loop diuretics are added to a regimen of spironolactone. Thepharmacokinetics and pharmacodynamics of loop diuretics have been amplyquantified in patients with cirrhosis. Unless patients have diminishedrenal function, they deliver normal amounts of diuretic into the urine( 32, 34, 52, 90, 96, 98 ). Thus a diminished response inpatients with cirrhosis occurs by pharmacodynamic mechanisms, whereinthe relationship between excretion rates of diuretic and natriureticresponse is shifted downward and to the right so that the response to amaximally effective dose is substantially less than occurs normally( 32, 34, 52, 90, 96, 98 ). As was discussed above withnephrotic syndrome, the cause of this shift is unknown. It may entailincreased solute reabsorption more proximal and/or more distal to theloop of Henle but also may imply changes at the loop itself.- F& z; H, a8 W' N0 B1 y

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 patientswith overt heart failure likely have gut wall edema causing diureticmalabsorption; studies have shown that the same quantity of loopdiuretic is absorbed in such patients as occurs in healthy controlsubjects ( 6, 13, 92, 95 ). Thus malabsorption does notoccur. However, the rate of absorption is slowed, particularly inpatients with decompensated heart failure; therefore, the time ofmaximal response is delayed to 4 h or more ( 95 ).Whether this change is important clinically has not been studied.
* Y8 {9 L+ q; F' w
Because the pharmacokinetics of loop diuretics are essentially normalin patients with heart failure, it is pharmacodynamic mechanisms thataccount for diminished response ( 12, 94 ). In fact,patients with heart failure have a pattern of response that is similarto that of patients with nephrotic syndrome or those with cirrhosis,with a shift in the relationship between diuretic excretion rate andresponse downward and to the right ( 12 ). In patients withmild-to-moderate heart failure, this results in a natriuretic responsein these patients that is one-fourth to one-third that which occursnormally to maximally effective doses of loop diuretics ( 12, 94 ). The response in patients with more severe disease issmaller yet. The response is not improved by large doses of loopdiuretic; the therapeutic strategy is to administer modest doses morefrequently (Table 2 ).* x: o3 T- W  \3 n/ t

Many patients with heart failure do not respond adequately to a loopdiuretic alone even if accompanied by dietary sodium restriction. Insuch patients, a thiazide diuretic is often added, wherein it is notuncommon for patients to have a synergistic response with a profounddiuresis ( 26, 27, 73, 87 ). The mechanism of this synergyis that discussed above in terms of the pathophysiology of chronictolerance to loop diuretics. The hypertrophied distal nephrons are thesite of action of thiazide diuretics so that their blockade results insubstantial natriuresis ( 25-27, 50, 60, 63, 87, 88 ).
* a) g0 R9 \" g% ]* P& r; N
In summary, patients with congestive heart failure have normal deliveryof loop diuretics into the urine and do not require large doses;rather, doses must be given more frequently (Table 2 ). The possiblemechanisms of the altered pharmacodynamics are as were discussedpreviously; particularly intriguing is the possibility of alteredexpression and/or activity of Na-K-2Cl transporters and the potentialrole of vasopressin therein.

SUMMARY

The pharmacokinetics and clinical pharmcodynamics of loopdiuretics have been well characterized in all the edematous disorders in which they are used. Such data allow more rational designs oftherapeutic regimens than was possible in the past. More recent data onthe receptor for loop diuretics, namely, the Na-K-2Cl transporter,offer the exciting prospect of linking changes in expression and/orfunction of this transporter to pharmacodynamic observations. Doing soshould allow even better therapeutic strategies in the future. Morespecifically, questions that are highly pertinent are whether alteredexpression and activity of the transporter occur in models of heartfailure, cirrhosis, and nephrotic syndrome and by which mechanism(s)that increase occurs. In particular, what is the role of nonosmoticallyreleased vasopressin? Is the function of the transporter altered? Ifso, what are the mediators of such changes and the implications thereinfor therapeutic strategies? Most importantly, the tools are now in handto dissect these mechanisms and attack these common clinical conditionsfrom a mechanism-based strategy as opposed to the more empiricalapproaches that have heretofore characterized this area.! Y; ]! _* e$ A  J% V3 O2 [) J8 P

ACKNOWLEDGEMENTS0 l5 D# L, X- v/ [- j

This work was supported by the General Clinical Research Center(MO1 RR-00750) and by National Institutes of Health Grants R01-DK-37994and R01-AG-07631.
      【参考文献】
1. Agarwal, R,Gorski JC,Sundblad K,andBrater DC. Urinary protein binding does not affect response to furosemide in patients with nephrotic syndrome. J Am Soc Nephrol 11:1100-1105,2000 .
8 f, b# `3 M3 U
/ z& m* v- O; g9 f1 B
4 S/ i9 p5 |' ]
2. Agre, P. Homer W. Smith award lecture. Aquaporin water channels in kidney. J Am Soc Nephrol 11:764-777,2000 .
( T% I( M9 L4 y* G7 b3 k

3. Akcicek, F,Yalniz T,Basci A,Ok E,andMees 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,andWilcox CS. A volume-independent component to postdiuretic sodium retention in humans. J Am Soc Nephrol 3:1878-1883,1993 .

! v: w7 G+ x/ T! ^& e
$ z  m% y) f& j
5. Andreasen, F,andMikkelsen E. Distribution, elimination and effect of furosemide in normal subjects and in patients with heart failure. Eur J Clin Pharmacol 12:15-22,1977  .
8 ~" y0 |" {# y5 Q- _
$ _. E) J. `( B- R7 Q

6. Bailie, GR,Grennan A,andWaldek S. Bioavailability of bumetanide in grossly oedematous patients. Clin Pharmacokinet 12:440-443,1987  .

+ Q; n) ]+ g( v
1 l# e6 F; @" g# Q  I4 O& i
7. Beerman, B. Aspects on pharmacokinetics of some diuretics. Acta Pharmacol Toxicol 54:17-32,1984.# b+ k& A* t8 |0 d
1 D9 l4 ]4 T. Q3 s) \

8. Beerman, B,Dalen E,andLindström B. Elimination of furosemide in healthy subjects and in those with renal failure. Clin Pharmacol Ther 22:70-78,1977  .

' S: ^% S+ i* f% `
' L4 F7 ?  E& V( `, c$ m( \( a
9. Brater, DC. Diuretic pharmacokinetics and pharmacodynamics.In: The In Vivo Study of Drug Action. Principles and Applications of Kinetic-Dynamic Modelling. Amsterdam: Elsevier, 1992.7 w2 R& d- J/ V) v
4 i& l% h8 u& k0 e& v

; c5 h5 b0 d0 y" @3 e3 N* ~+ E
10. Brater, DC. Diuretic therapy. N Engl J Med 339:387-395,1998 .

. o5 j9 f& A; r! i; I, N6 s
' D2 K! m7 f4 [0 P( F
11. Brater, DC,Chennavasin P,Day B,Burdette A,andAnderson S. Bumetanide and furosemide. Clin Pharmacol Ther 34:207-213,1983  .

6 Q; @1 ^8 V" ]( Q4 l# a! M3 L

12. Brater, DC,Chennavasin P,andSeiwell R. Furosemide in patients with heart failure: shift in dose-response curves. Clin Pharmacol Ther 28:182-186,1980  .1 Y& J& e7 I. B  t* @+ a

13. Brater, DC,Day B,Burdette A,andAnderson S. Bumetanide and furosemide in heart failure. Kidney Int 26:183-189,1984  .3 U, y9 n. R9 F; S6 w% m  o
: d" `- P# w9 `, u6 Y9 q

; n- Y! o. a  ]1 f$ ]6 T4 \8 e
14. Brater, DC,Leinfelder J,andAnderson SA. Clinical pharmacology of torsemide, a new loop diuretic. Clin Pharmacol Ther 42:187-192,1987  .# Z4 x5 u" z, T$ j' `8 w
$ H9 ]& `5 |9 _$ o2 w
, j7 }0 Q: L; P0 J6 o; A
4 m/ r! B9 x7 Q- U" H  V/ _! k
15. Burg, MB. Tubular chloride transport and the mode of action of some diuretics. Kidney Int 9:189-197,1976  ., V' i' M# S7 T9 ]
9 |! x6 x6 A( j/ X% B  ^

16. Carmichael, J,andShankel SW. Effects of nonsteroidal anti-inflammatory drugs on prostaglandins and renal function. Am J Med 78:992-1000,1985  .- n1 K& ~1 d+ K' b" \. `

17. Chalasani, N,Gorski JC,Horlander JC, Sr,Craven R,Hoen H,Maya J,andBrater DC. Effects of albumin/furosemide mixtures on responses to furosemide in hypoalbuminemic patients. J Am Soc Nephrol 12:1010-1016,2001 .& |- A1 \" D3 w; v
. d5 \1 ]; a$ v0 g* r9 x

8 [# Q; H# o2 g4 k8 M1 K
18. Chaturvedi, PR,O'Donnell JP,Nicholas JM,Shoenthal DR,Waters DH,andGwilt PR. Steady state absorption kinetics and pharmacodynamics of furosemide in congestive heart failure. Int J Clin Pharmacol Ther Toxicol 25:123-128,1987 .! Q* l5 F. U( x2 T; n0 f
# N; Q0 _' n  [
6 ^) @' h2 G4 [4 t1 ]6 ?' d- b

19. Chennavasin, P,Seiwell R,Brater DC,andLiang WM. Pharmacodynamic analysis of the furosemide-probenecid interaction in man. Kidney Int 16:187-195,1979  .# i. Q1 k: ]; p" Y) B

8 j+ a# b' e9 O7 _/ W: o8 e

20. Clive, DM,andStoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med 310:563-572,1984  .

21. Cutler, RE,Forrey AW,Christopher TG,andKimpel BM. Pharmacokinetics of furosemide in normal subjects and functionally anephric patients. Clin Pharmacol Ther 15:588-596,1974  .2 z/ J7 z- w4 Y$ y

  e4 F3 _* J' c, F

22. Davies, DL,Lant AF,Millard NR,Smith AJ,Ward JW,andWilson GM. Renal action, therapeutic use, and pharmacokinetics of the diuretic bumetanide. Clin Pharmacol Ther 15:141-155,1974  .; N9 k+ m  q4 v6 t
5 h: T8 `  M& d% L* k! D0 ^$ C9 h
& ]8 T/ _+ t3 ?9 W. f5 i
+ L, m( C0 r* U# ~! G
23. Dormans, TP,van Meyel JJ,Gerlag PG,Tan Y,Russel FG,andSmits P. Diuretic efficacy of high dose furosemide in severe heart failure: bolus injection versus continuous infusion. J Am Coll Cardiol 28:376-382,1996 .

8 ~* k" v7 t( C% }6 N# l+ q  }

24. Ecelbarger, CA,Yu S,Lee AJ,Weinstein LS,andKnepper MA. Decreased renal Na-K-2Cl cotransporter abundance in mice with heterozygous disruption of the G s gene. Am J Physiol Renal Physiol 277:F235-F244,1999 .. v) c4 z% ~4 g. Q9 C% z! _

3 ~8 B0 D* [! H' u, J" A3 r

25. Ellison, DH,Velazquez H,andWright 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  .& W# B6 G" p# D$ r% s8 K) u" \; m
& h' i# a( I" |7 y: X

3 \3 B* n  m" A
26. Ellison, DH. The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med 114:886-894,1991  .
3 b8 t7 K/ Y9 ^7 T
$ k2 w  f5 r: R* g# `- H

27. Epstein, M,Lepp B,Hoffman D,andLevinson R. Potentiation of furosemide by metolazone in refractory edema. Curr Ther Res 21:656-667,1977.
0 ]) q" h" ]* b+ P5 ?: H0 E

2 P2 B7 q+ i+ w! J3 \5 j6 {
28. Ferguson, JA,Sundblad KJ,Becker PK,Gorski JC,Rudy DW,andBrater DC. Role of duration of diuretic effect in preventing sodium retention. Clin Pharmacol Ther 62:203-208,1997  .9 v( [3 L. B" V

' {( F0 d: _' X

29. Fernandez-Llama, P,Ecelbarger CA,Ware JA,Andrews P,Lee AJ,Turner R,Nielsen S,andKnepper 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 .1 g. e  {* y2 `" a
. z1 A; R, J7 o1 O* K

30. Fliser, D,Zurbruggen I,Mutschler E,Bischoff I,Nussberger J,Franek E,andRitz E. Coadministration of albumin and furosemide in patients with the nephrotic syndrome. Kidney Int 55:629-634,1999  .
: g4 F+ C; t4 b

31. Forbush, B, III,andPalfrey HC. [ 3 H]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 .0 l, Y* {& D" Z8 f

/ @/ k- D3 ~1 H  P1 t9 \8 Q

32. Fuller, R,Hoppel C,andIngalls ST. Furosemide kinetics in patients with hepatic cirrhosis with ascites. Clin Pharmacol Ther 30:461-467,1981  .  G) {0 k7 _, a; w8 q+ w
$ y: E/ s( e. h; e3 D! i
4 }1 p$ k. t* `- ?" S

33. Gallagher, KL,andJones JK. Furosemide-induced ototoxicity. Ann Intern Med 91:744-745,1979  .

- U4 U# C! e4 v
. _. ^( ~3 R+ j+ J4 ?+ \2 c
34. Gehr, TW,Rudy DW,Matzke GR,Kramer WG,Sica DA,andBrater DC. The pharmacokinetics of intravenous and oral torsemide in patients with chronic renal insufficiency. Clin Pharmacol Ther 56:31-38,1994  .- t$ K% [: e: G3 t% }) ?* O: g
2 i: V( C' b; h; H9 b

35. Gerlag, PG,andvan Meijel JJ. High-dose furosemide in the treatment of refractory congestive heart failure. Arch Intern Med 148:286-291,1988 .

36. Gimenez, I,Isenring P,andForbush 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 .9 Q5 H+ v" q) H$ J
% t: K" x4 m* U% z  @: m
9 m4 X; b7 Z0 d$ d
0 V: ?+ [7 }9 b, J8 l, {1 B
37. Green, TP,andMirkin BL. Resistance of proteinuric rats to furosemide: urinary drug protein binding as a determinant of drug effect. Life Sci 26:623-630,1980  .8 H* s& m( v0 ~  `3 i: @
" x/ _0 }2 f; F

) v* C- y1 i2 J; W" X& u& B
38. Green, TP,andMirkin 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 .( L5 J7 H4 \: a
4 }/ C5 _0 D( e, [! }% d
! N$ U" X" Q/ R% d: G0 M

39. Greither, A,Goldman S,Edelen JS,Benet LZ,andCohn K. Pharmacokinetics of furosemide in patients with congestive heart failure. Pharmacology 19:121-131,1979  .5 T% k6 C$ I9 [2 S
" I8 z/ H0 \# y, f# l# Q
! A% P5 ~: v( B) F  Y' v

40. Haas, M,andForbush B, III. Na,K,Cl-cotransport system: characterization by bumetanide binding and photolabelling. Kidney Int Suppl 23:S134-S143,1987 .
, g3 D! _$ i& w7 T/ C

5 w/ k. }/ L! j% O0 ^/ [
41. Haas, M,andForbush B, III. The Na-K-Cl cotransporters. J Bioenerg Biomembr 30:161-172,1998  .8 g/ J( y* ]. _% ?+ i
6 M, C2 t# j% q5 [  x

42. Haas, M,andForbush B, III. The Na-K-Cl cotransporter of secretory epithelia. Annu Rev Physiol 62:515-534,2000  .& t5 \! B) {8 f3 T4 A. }

5 }: k: P2 ]5 B
43. Hammarlund, MM,Odlind B,andPaalzow LK. Acute tolerance to furosemide diuresis in humans. Pharmacokinetic-pharmacodynamic modeling. J Pharmacol Exp Ther 233:447-453,1985 .* Z  r9 J8 `' Y5 ?. P. I9 v& q! u
0 \9 N! y2 o, m$ Y7 N8 R% _
8 d" ^! Y3 A/ B- P% t  U

44. Hebert, RL,Jacobson HR,andBreyer MD. PGE 2 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 .& K; n8 o/ o8 g! @! V

2 |" v/ S5 X! R1 k
3 y/ }' N7 O$ {3 o8 p
45. Heerdink, ER,Leufkens HG,Herings RM,Ottervanger JP,Stricker BH,andBakker A. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med 158:1108-1112,1998 .
+ K0 h. {; z6 u: r

46. Holazo, AA,Colburn WA,Gustafson JH,Young RL,andParsonnet M. Pharmacokinetics of bumetanide following intravenous, intramuscular, and oral administrations to normal subjects. J Pharm Sci 73:1108-1113,1984  .

47. Huang, CM,Atkinson AJ, Jr,Levin M,Levin NW,andQuintanilla A. Pharmacokinetics of furosemide in advanced renal failure. Clin Pharmacol Ther 16:659-666,1974  .; T$ d- C  t. h. W% I

48. Inoue, M,Okajima K,Itoh K,Ando Y,Watanabe N,Yasaka T,Nagase S,andMorino Y. Mechanism of furosemide resistance in analbuminemic rats and hypoalbuminemic patients. Kidney Int 32:198-203,1987  .
0 d6 l: Z1 f2 }  j2 n4 N8 D

* `) g6 x. A9 z5 f
49. Isenring, P,Jacoby SC,Payne JA,andForbush 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 .* s  y) H9 ^+ o4 Q

! w' H6 y$ k# ]

50. Kaissling, B,andStanton 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 .

( o! @9 q/ R& p: U
51. Kaojarern, S,Chennavasin P,Anderson S,andBrater 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 .

( m9 @) M3 t, E
8 y( l3 M5 n  K5 g
52. Keller, E,Hoppe-Seyler G,Mumm R,andSchollmeyer P. Influence of hepatic cirrhosis and end-stage renal disease on pharmacokinetics and pharmacodynamics of furosemide. Eur J Clin Pharmacol 20:27-33,1981  .

6 D* x  K# C' w; y
53. Keller, E,Hoppe-Seyler G,andSchollmeyer P. Disposition and diuretic effect of furosemide in the nephrotic syndrome. Clin Pharmacol Ther 32:442-449,1982  .

/ O' a( O% `, A* h4 S2 k
54. Kelly, RA,Wilcox CS,Mitch WE,Meyer TW,Souney PF,Rayment CM,Friedman PA,andSwartz SL. Response of the kidney to furosemide. II. Effect of captopril on sodium balance. Kidney Int 24:233-239,1983  .' p+ q0 T) L' T6 a) u+ [. s. [
- U5 `9 X# M/ @3 y

55. Kim, GH,Ecelbarger CA,Mitchell C,Packer RK,Wade JB,andKnepper 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 .

$ x8 g* J% ?) X

56. Kirchner, KA,Voelker JR,andBrater 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 .

; {, x) r" w4 F* J& R) B& {3 P
" d/ i8 X. L6 l- b( B0 F
57. Kirchner, KA,Voelker JR,andBrater DC. Binding inhibitors restore furosemide potency in tubule fluid containing albumin. Kidney Int 40:418-424,1991  .
( Q. r0 S2 f4 u
/ ?3 T! Z1 b  K' r6 t4 {& h- N/ L

58. Kirchner, KA,Voelker JR,andBrater DC. Tubular resistance to furosemide contributes to the attenuated diuretic response in nephrotic rats. J Am Soc Nephrol 2:1201-1207,1992 .  ^# h& }0 b9 @' a+ o7 n) [

0 r0 o+ l4 v0 z0 u
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 .4 v+ l' i( n) P8 Z/ p' j- n

4 J9 h8 L2 ^1 O* G3 y9 f* S: P- O
* A# Y7 F+ x: w* f
60. Kobayashi, S,Clemmons DR,Nogami H,Roy AK,andVenkatachalam 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  .

4 V- l2 m- ], v$ W. G! E
61. Kramer, WG,Smith WB,Ferguson J,Serpas T,Grant AG, III,Black PK,andBrater 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 .. I' `0 U! q1 U1 L+ f

62. Lahav, M,Regev A,Ra'anani P,andTheodor E. Intermittent administration of furosemide vs. continuous infusion preceded by a loading dose for congestive heart failure. Chest 102:725-731,1992 .

! [. S% u  K# n  O* w
! S) b3 J- Q2 ^
63. Loon, NR,Wilcox CS,andUnwin RJ. Mechanism of impaired natriuretic response to furosemide during prolonged therapy. Kidney Int 36:682-689,1989  .
, N/ w$ M5 `$ z( v  ^3 o8 d

64. Martinez-Maldonado, M,andCordova HR. Cellular and molecular aspects of the renal effects of diuretic agents. Kidney Int 38:632-641,1990  .
8 e3 S8 R3 Y( V; ]8 e" f: }

65. Merlo, J,Broms K,Lindblad U,Bjorck-Linne A,Liedholm H,Ostergren PO,Erhardt L,Rastam L,andMelander 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  .4 B- d, V6 |) z  y) o
0 N# B$ o* X5 Y3 A0 I

66. Mount, DB,Baekgaard A,Hall AE,Plata C,Xu J,Beier DR,Gamba G,andHebert 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 .8 T9 Y) m: R: ]7 `' ]7 k* K: H
) L6 f- [+ }0 Y+ h: l# X: n# v0 ?

: Y, y  I5 s; }; q, W; e; ~* Y+ [
67. Murray, MD,Deer MM,Ferguson JA,Dexter PR,Bennett SJ,Perkins SM,Smith FE,Lane KA,Adams LD,Tierney WM,andBrater DC. Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. Am J Med 111:513-520,2001  .
( t3 r+ Q% G% q; K8 a' _

68. Murray, MD,Haag KM,Black PK,Hall SD,andBrater DC. Variable furosemide absorption and poor predictability of response in elderly patients. Pharmacotherapy 17:98-106,1997  .' R3 E7 O6 _5 _, E+ g: O; m6 ?% d
" H4 W( m/ a* W- d0 E
% w+ B; p- g' i- r4 ~9 }( I7 h! {  P

69. Nielsen, S,Maunsbach AB,Ecelbarger CA,andKnepper 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 .

, b8 i) w0 A  w& p$ F
70. Obermuller, N,Kunchaparty S,Ellison DH,andBachmann 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  .
. u) r( ?" V  U$ m6 `- \
8 g0 y- A5 O" |
& o- M/ g9 _8 v9 T+ n5 v/ e* S
71. Odlind, B,andBeermann B. Renal tubular secretion and effects of furosemide. Clin Pharmacol Ther 27:784-790,1980  .$ q7 ]0 _# x' J

+ i( `- ~4 l) W5 l6 P# G' T
) [& P6 D: ~- U
72. Olesen, KH,andSigurd 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  .5 {" m- d/ x3 z- L. A8 c$ j( S

; H& e. R- \  k
  r) b( L: P" h1 ?5 q
73. Oster, JR,Epstein M,andSmoller S. Combined therapy with thiazide-type and loop diuretic agents for resistant sodium retention. Ann Intern Med 99:405-406,1983  .8 _1 y, ]. Z% K1 x
4 p. y* K0 k2 T. _& Y& I
6 k) m# y# x0 X& x' u' c5 m
. H3 ?" o$ C# t" ^8 c7 z  @9 J
74. Perez, J,Sitar DS,andOgilvie RI. Kinetic disposition and diuretic effect of frusemide in acute pulmonary oedema. Br J Clin Pharmacol 9:471-478,1980  .

7 |- E0 C  ]1 u# T% ?: G* z6 S
75. Petersen, JS,Shalmi M,Abildgaard U,Christensen NJ,andChristensen S. Renal effects of alpha-adrenoceptor blockade during furosemide diuresis in conscious rats. Pharmacol Toxicol 70:3-12,1992  .
" c  Q( A) h% {& s' u
' P2 v0 b( Y7 Q( t$ _, v" v
/ i0 t; a0 M) t+ t; `' z
76. Pichette, V,anddu Souich P. Role of the kidneys in the metabolism of furosemide: its inhibition by probenecid. J Am Soc Nephrol 7:345-349,1996 .

77. Plato, CF,Stoos BA,Wang D,andGarvin JL. Endogenous nitric oxide inhibits chloride transport in the thick ascending limb. Am J Physiol Renal Physiol 276:F159-F163,1999 .
4 ?' t6 s4 P" g; n& Q7 i
: S1 i' \, o. }8 K

78. Popowicz, P,andSimmons 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 .3 E1 Y2 m/ f/ L, Q* C

79. Rane, A,Villeneuve JP,Stone WJ,Nies AS,Wilkinson GR,andBranch RA. Plasma binding and disposition of furosemide in the nephrotic syndrome and in uremia. Clin Pharmacol Ther 24:199-207,1978  .2 [$ |7 ^5 v; K0 r" F% v

& c+ {" s/ e  [% M% w% K

80. Rose, BD. Diuretics. Kidney Int 39:336-352,1991  .
0 @, @6 {2 C+ H9 u4 w6 t. K0 J

: X, Z- c: c2 K: ]
81. Rudy, DW,Gehr TW,Matzke GR,Kramer WG,Sica DA,andBrater DC. The pharmacodynamics of intravenous and oral torsemide in patients with chronic renal insufficiency. Clin Pharmacol Ther 56:39-47,1994  .

/ f2 i$ r: U9 y' H; _" ]
5 r! s7 h/ h1 b% F6 r6 s
82. Rudy, DW,Voelker JR,Greene PK,Esparza FA,andBrater DC. Loop diuretics for chronic renal insufficiency: a continuous infusion is more efficacious than bolus therapy. Ann Intern Med 115:360-366,1991  .9 \; Y: R- ?$ Q
% t9 b" M% e  D, Y" @: A5 w
5 K5 e* _6 R# z

83. Schlondorff, D. Renal complications of nonsteroidal anti-inflammatory drugs. Kidney Int 44:643-653,1993  .

84. Schrier, RW,andBerl T. Nonosmolar factors affecting renal water excretion (second of two parts). N Engl J Med 292:141-145,1975  .: B  x$ v1 w0 J
, l5 u. O' P( K2 g' J0 R
* U2 @5 K. o; Z
- K, `  @4 A3 v, n3 J1 @
85. Schrier, RW,andBerl T. Nonosmolar factors affecting renal water excretion (first of two parts). N Engl J Med 292:81-88,1975  .
  q7 D/ s4 D( O+ c
4 K0 J( C: y5 X, @
4 `0 I% N) ^) Y& r; \6 c
86. Schwartz, S,Brater DC,Pound D,Green PK,Kramer WG,andRudy D. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide in patients with cirrhosis. Clin Pharmacol Ther 54:90-97,1993  .$ r9 a+ j6 h5 w- i) S" W

4 {! n( x8 \3 D
) `$ ^2 e; V. o7 K
87. Sica, DA,andGehr TW. Diuretic combinations in refractory oedema states: pharmacokinetic-pharmacodynamic relationships. Clin Pharmacokinet 30:229-249,1996  .; {) q& _+ b4 V4 c" q) |
& h% n, n& ]/ S8 F7 r+ G' }  G

, ?0 p3 j9 J, u4 L: s8 |" m2 }8 x" }  r
88. Stanton, BA,andKaissling 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 .
8 X! L! ~3 F$ t
/ t$ ?. r" X5 f/ X# {: I' x

89. Tilstone, WJ,andFine A. Furosemide kinetics in renal failure. Clin Pharmacol Ther 23:644-650,1978  .$ [4 G9 ^% E+ f

90. Traeger, A,Hantze R,Penzlin M,Krombholz B,Reinhardt M,Keil E,andJorke D. Pharmacokinetics and pharmacodynamic effects of furosemide in patients with liver cirrhosis. Int J Clin Pharmacol Ther Toxicol 23:129-133,1985 .& F, H$ u5 P: S

91. Van Meyel, JJ,Gerlag PG,Smits P,Russel FG,Tan Y,Van Ginneken CA,andGribnau FW. Absorption of high dose furosemide (frusemide) in congestive heart failure. Clin Pharmacokinet 22:308-318,1992  .
4 }5 l  A) h5 E- b: J& k' M
# o0 ]/ n. I5 [1 \
3 X" h# |- L( y
92. Van Meyel, JJ,Smits P,Dormans T,Gerlag PG,Russel FG,andGribnau FW. Continuous infusion of furosemide in the treatment of patients with congestive heart failure and diuretic resistance. J Intern Med 235:329-334,1994  .: q7 Z& N0 L$ `9 V  C- I
$ a3 m$ i! Z( [& A% C# Q& w' w3 J

93. Van Olden, RW,van Meyel JJ,andGerlag PG. Sensitivity of residual nephrons to high dose furosemide described by diuretic efficiency. Eur J Clin Pharmacol 47:483-488,1995  .

3 I' b: T1 P# x$ Z$ I' a1 j% M
8 P* Y+ K4 \0 |6 A
94. Vargo, DL,Kramer WG,Black PK,Smith WB,Serpas T,andBrater DC. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide and furosemide in patients with congestive heart failure. Clin Pharmacol Ther 57:601-609,1995  .
' _' ^1 A  L3 g4 r# R

95. Vasko, MR,Cartwright DB,Knochel JP,Nixon JV,andBrater DC. Furosemide absorption altered in decompensated congestive heart failure. Ann Intern Med 102:314-318,1985  .
8 U  e6 K( i3 b$ W
2 U& ]: v  e( a7 q' s! p- Q, M
; C% _1 X2 Y9 U8 R, L: D
96. Verbeeck, RK,Patwardhan RV,Villeneuve JP,Wilkinson GR,andBranch RA. Furosemide disposition in cirrhosis. Clin Pharmacol Ther 31:719-725,1982  .
- k/ Z: y1 \0 C! D: }! A. S
( b% u) H" Z: c- T, Z

97. Verkman, AS,andMitra AK. Structure and function of aquaporin water channels. Am J Physiol Renal Physiol 278:F13-F28,2000 .- P0 {' u3 m/ K+ @$ o% o1 g
8 `6 {( z  P* A& k, i% i

98. Villeneuve, JP,Verbeeck RK,Wilkinson GR,andBranch RA. Furosemide kinetics and dynamics in patients with cirrhosis. Clin Pharmacol Ther 40:14-20,1986  .

) s2 g+ c1 D8 {  E( \

99. Voelker, JR,Cartwright-Brown D,Anderson S,Leinfelder J,Sica DA,Kokko JP,andBrater DC. Comparison of loop diuretics in patients with chronic renal insufficiency. Kidney Int 32:572-578,1987  .( I1 U/ S4 |; t# @) G0 i

100. Wakelkamp, M,Alvan G,Gabrielsson J,andPaintaud G. Pharmacodynamic modeling of furosemide tolerance after multiple intravenous administration. Clin Pharmacol Ther 60:75-88,1996  .) b4 Y; `3 m6 @, |: h
) o# O+ n/ E' t8 u1 S0 U: p9 C

! Z, J! p# R4 _8 w1 p; J
101. Wilcox, CS,Guzman NJ,Mitch WE,Kelly RA,Maroni BJ,Souney PF,Rayment CM,Braun L,Colucci R,andLoon NR. Na  , K  , and BP homeostasis in man during furosemide: effects of prazosin and captopril. Kidney Int 31:135-141,1987  .3 P( e) O5 m- g4 A5 v$ o

102. Wilcox, CS,Mitch WE,Kelly RA,Skorecki K,Meyer TW,Friedman PA,andSouney PF. Response of the kidney to furosemide. I. Effects of salt intake and renal compensation. J Lab Clin Med 102:450-458,1983  .
! l( o2 v3 [$ h* \+ y

103. Yamamoto, T,andSasaki S. Aquaporins in the kidney: emerging new aspects. Kidney Int 54:1041-1051,1998  .

收藏0 分享0 顶0 踩0