the efficacy of diuretics in acute and chronic renal failure

Drugs 41 (Suppl. 3): 69-79, 1991

0012-6667/91 /0300-0069/$5.50/0

© Adis International Limited All

rights reserved.

DRSUP2 139a

The Efficacy of Diuretics in Acute and Chronic Renal Failure Focus on Torasemide

T. Risler, B. Kramer and G.A. MilllerSection of Nephrology and Hypertension, Department of Medicine III . University of Tubingen. Tubingen, Federal Republic of Germany

Summary Loop diuretics in high doses are the drugs of choice in the treatment of both acute renal failure (ARF) and chronic renal failure (CRF). Their pharmacokinetic and phar-macodynamic properties give them a high efficacy, even in severely compromised renal function. The serum elimination half-life and duration of action of most loop diuretics are dependent on the glomerular filtration rate and are therefore prolonged in renal fail-ure. Torasemide, a new high ceiling and long acting loop diuretic, is as potent as furo-semide (frusemide) in patients with advanced renal failure. Unlike other loop diuretics the half-life and duration of action of torasemide are not dependent on renal function and the parent drug does not accumulate in renal failure. The extent of metabolism is clinically negligible. A number of studies have demonstrated the efficacy of furosemide bumetanide, piretanide and torasemide in patients with ARF and CRF. When compared with the other loop diuretics, torasemide has the following advantages: a longer half-life independent of renal function, no indications of toxic side effects and apparently less influence on calciuresis.

Acute renal failure (ARF) is characterised by a rapid deterioration of renal function, resulting in progressive azotaemia. Although oliguria (urine output < 400 ml/24h) is a common feature of ARF, there have been some exceptions (nonoliguric or polyline ARF) [Maharaj 1988].

Chronic renal failure (CRF) is a syndrome which results from progressive and irreversible destruc-tion of the nephron, regardless of the underlying cause. It is defined by a reduced glomerular filtra-tion rate (GFR) for > 3 to 6 months. The inter-individual variety in the severity of the signs and symptoms of uraemia may be great, depending on the magnitude of renal failure.

Diuretics are of special importance in the treat-

ment of both ARF and CRF. Traditionally high dose loop diuretics, mannitol, or both are used either to prevent oliguric ARF or to convert it into nonoliguric rena failure. which is easier to manageclinically (Levine 1989). However, there are few controlled studies to support this practice and it is still uncertain whether diuretics can alter the course of oliguric ARF.

In CRF loop diuretics in high doses are valu-able in the management of associated fluid roten-tion and hypertension.

For the treatment of ARF and CRF an ideal diuretic should:

• increase renal volume and sodium excretion, in

70 Drugs 41 (Suppl.3) 1991

a dose-dependent manner, even when the GFR is as low as 5 ml/min:• leave calcium and potassium excretion undis-turbed;• be excreted and metabolised independently ofrenal function;• have no toxic side effects even in high doses;• not be eliminated via haemodialysis.

Torasemide is a new high ceiling loop diureticwhich, compared with furosemide (frusemide), has a longer elimination half-life, a long duration of action and a nearly complete bioavailability [De-large 1988; Lesne 1988; Neugebauer et al. 1988]. The properties of torasemide will be compared with other available loop diuretics according to the prin-ciples listed above. The role of loop diuretics in general, their indications, pharmacokinetic and pharmacodynamic properties and their clinical use will be reviewed in this paper.

1. Available Diuretics for the Treatmentof Renal Failure

Renal physiologists have elucidated the mode of action of almost all diuretics in animal models (Greger & Schlatter 1983; Oberleithner et al. 1982). According to their mode of action, diuretic sub-stances can be divided into different groups, not all of which are appropriate for use in renal failure.

The osmotic diuretics interfere with the capac-ity of the proximal tubule, the ascending limb of the loop of Henle, and the collecting ducts to reab-sorb water. Osmotically active but nonreabsorba-ble sugars such as mannitol bind water and thus impede its reabsorption. These substances are pri-marily used to treat ARF. Hanley and Davidson (1981), among others, demonstrated a protective effect of mannitol on the development of ARF in their animal model. However, this preventive effect has not yet been confirmed in clinical medi-cine despite many studies.

Beall et al. (1965) attributed the beneficial effect of mannitol more to the increase in diuresis than glomerular filtration. This proposal alone justifies a trial with osmotic diuretics in order to transform an oliguric into a polyuric renal failure.

The dosage should be restricted to prevent a large amount of psmotically active material being left in the circulation in case of therapeutic failure

Mannitol is very difficult to remove, even with dialysis.

Osmotic diuretics have only a few and some-what debatable indications in CRF (Rodrigo et al. 1977). Mannitol may be used to prevet hypoten-sion and muscle cramps in patients on haemodi-alysis who present with a massive fluid overload Dialysis dysequilibrium syndrome may be allevi-ated by mannitol in severely uraemic patients.

Drugs inhibiting the proxinnal tubular carboan-hydrase reduce sodium bicarbonate reabsorption and enhance water and salt excretion. Metabolic acidosis, often accompanying renal failure, reduces the availability of bicarbonate and thus inhibits this class of diuretic. Therefore, carboanhydrase inhib-itors are ineffective in renal failure.

Thiazides and analogous substances increasediuresis by inhibiting sodium reabsorption in thedistal tubule. These drugs are of minor importancein the treatment of patients with renal failure astheir effectiveness diminishes when the GFR is <30 ml/min. Nevertheless, they may have clinicalimportance by enhancing the effect of loop diuretics in terminal renal failure when given concomi-cantly. Loop diuretics improve the distal deliveryof sodium and thus allow thiazides to act more effectively (Wollam et al. 1982).

Some related substances, such as xipamide, have properties that place them between thiazides and loop diuretics (Krömer & Rister 1988). They are effective even in severe renal failure.

Potassium-retaining diuretics reduce potassium excretion dependent on and independent of aldo-sterone in the distal part of the distal convoluted tubule and the proximal collecting ducts.

This group of less effective diuretics is often combined with thiazides for patients with hyper-tension or cardiac failure. Their potassium-retain-ing properties may increase dramatically in renal failure and thus generate dangerous hyperkalae-mia. Therefore, these substances have no place in the therapy of patients with ARF and CRF.

Loop diuretics reduce sodium choride reab-

Efficacy of Diuretics in Acute and Chronic Renal Failure 71

sorption mainly in the thick ascending limb of Henle's loop, but also in the proximal tubule (as a consequence of parallel increases in osmolar clear-ance and bicarbonate excretion). This group of di-aretics is mainly indicated in renal failure, because of the marked effect in reduced renal function. Thus, only loop diuretics meet the basic require-ments for use in ARF and CRF.

1.1 Loop Diuretics in Acute Renal Failure

Animal experiments have demonstrated con-flicting results on the effect of the loop diuretic furosemide in the prevention of ARF (Baehler et al. 1977, De Torrente et al. 1978; Fink 1982). In are majority of these studies, loop diuretics in-creased urine production but did not improve renal function. Furosemide appears to protect the thick Escending limb of the loop of Henle by decreasing oxygen-consuming transport processes (Brezis et al. 1984), which may improve tolerance to hypoxia. Potential advantages of loop diuretics in ARF as summarised by tiller and Mudge (1980) include Dilution of toxins in the tubular lumen, increase of intratubular pressure with consequent removal of obstructions, enhanced potassium excretion and liberal water and electrolyte intake.

The few controlled clinical studies on the treat-ment of oliguric ARF (Brown et al. 1981: Canta-rovich et al. 1973; Epstein et al. 1975; Kleinknecht et al. 1976; Minuth et al. 1976) demonstrate that loop diuretics increase diuresis without improving renal function and prognosis, but greatly facilitate patient care. Use of very high doses has been as-sociated with irreversible deafness in some patients (Brown et al. 1981).

1.2 Loop Diuretics in Chronic Renal Failure

The choice of diuretics for use in ARF and CRFis restricted to loop diuretics, thiazide analogueswith similar properties, and osmotic diuretics. Allothers lose their effect in severely impaired renalfuction. Thus, the following discussion onpharmacology and clinical use will focus on thesedrugs and their indications.

Loop diuretics are the drugs of choice in patients with CRF. While a shortcut intense diuresis is ob-tained in patients with normal renal function, the diuretic effect is reduced and prolonged by the shrinking number of nephrons in renal failure. Fractional excretion of salt and water decreases with declining renal function. The effectiveness of loop diuretics is correlated with the total amount of fil -tered salt and water. All loop diuretics act from the luminal side of the tubule. Therefore, glomerular filtration. and free tubular secretion of these drugs is a prerequisite for their diuretic effect. Many dif-ferent substances and drugs compete for the tubular secretory system for weak organic acids. Thus, endogenous acids as well as drugs may impede tu-bular secretion of loop diuretics in renal failure.

Brater et al. (1986) calculated a dose-response curve for intravenous furosemide and demon-strated that a dose of > 160mg did not produce enhanced diuretic activity. These results call into question the prescribing of very high doses of loop diuretics in patients with a GFR of < 5 ml/min. The relationship between dose, effect and toxic side effects will be discussed later.

As well as their tubular action, loop diuretics may also enhance renal plasma flow (Higashio et al. 1978). Some investigators (Fritz et al. 1971) have used high doses to improve the GFR. These auth-ors consider that a direct effect on glomerular fil-tration is likely, but others disagree with those re-sults (Allison & Kennedy 1971). An increase in the GFR as a consequence of increased renal plasma flow may have been misinterpreted as an inde-pendent phenomenon.

In this paper, established loop diuretics (mainly furosemide, but also bumetanide and piretanide) will be compared with torasemide, a new member of the class.

2. Pharmacokinetics and Pharmacodynamics of Loop Diuretics in Renal Failure

The pharmacokinetic properties of loop diuret-ics are of primary importance in renal failure, be-cause they reach their site of action via glamerular filtration and mainly tubular secretion.

72 Drug 41 (Suppl.3) 1991

Fig. 1. Correlation of the amount of drug excreted into the urine (dotted lines) and sodium excretion (bars) for (a) torasemideand (b) furosemide (frusemide) after single intravenous administration. Time 0 denotes administration of the drugs.Urinewas collected during 0 to 6, 6 to 12, 12 to 24 hours on a preceding control day, the day after administration of the drug,and on the second day thereafter. * = significant differences from the respective collection period of the preceding contraday (adapted from Klutsch et al. 1988: Kult et al. 1990, with permission).

The bioavailability of furosemide is 40 to 65%

will wide intersubject variability in normal volun-teers (Beerrnann & Groschinsky-Grind 1980; Benet 1979). The bioavailability of bumetanide is cal-culated between 65 and > 90% (Holazo et al. 1984; lau et al. 1986; Marcantonio et al 1983) without major differences in renal failure. According to Marone et al. (1984), the bioavailability of pire-tanide is about 80%. For torasemide, bioavailability between 80 and 90% was demonstrated (Lesne 1988; Neugebauer et al. 1988).

The discrepancies between the findings from studies of the bioavailability of various loop di-uretics probably result from the different methods used to determine drug concentrations, and differ-ent dosages. Some authors suggest an influence of renal failure on bioavailability (Marcantonio et al. 1983; Tilstone & Fine 1978). Nevertheless, inter-individual differences are substantial. Thus, indi-vidual factors more than renal failure may account for the intraindividual variability in bioavailability and salidiuretic response. The serum protein bind-ing of diuretic drugs is a crucial consideration, since only the free fraction of the drug undergoes glo-merular filtration. All loop diuretics are avidly bound to serum albumin (Goto et al. 1980); thus, the main renal excretion mechanism of these drugs is tubular secretion. In renal failure, the protein-bound fraction decreases (Goto et al. 1980), which could facilitate access to the site of action inside the tubule. However, this effect is unlikely to become clinically significant, since, for loop diuretics eliminated mainly by the kidney, the terminal half-life is increased with the loss of renal function. The terminal half-life of furosemide has been reported to increase 3 times in functionally anephric patients (Keller et al. 1981). However, Cutler et al. (1974) demonstrated a less than doubled elimination half-life in an identical group of patients. Huang et al. (1974) calculated an even longer terminal half-life that was 10 times that of healthy controls. Similar findings were reported by Walter et al. (1985) for piretanide. The half-life increased up to 3-fold in patients with end-stage renal failure. Bumetanide is equalfy affected by a loss of renal function (Lau et al. 1986; Marcantonio et al. 1983). Torasemide,

however, is an exception; the diuretic efficacy of this new loop diuretic has been shown to be com-parable to furosemide in single-dose studies in patients with advanced renal failure using oral doses of torasemide 100, 200 and 400mg compared with furosemide 250 and 500mg and when torasemide 100 and 200mg and furosemide 100 and 200mg have been administered intravenously to patients with CRF (Grabensee et al. 1986; Klütsch et al.1988). A long acting salidiuretic effect was dem-onstrated for torasemide.

After intravenous administration, the ratio of equipotency of torasemide and furosemide was1: 1, in contrast to studies with volunteers or patients with acute heart failure where the ratio was found to be 1: 2 on a weight basis (Lesne 1988; Stroobandt et al. 1982). As demonstrated by Do-dion and Willems (1986), the elimination half-life of torasemide (3 to 4 hours) is independent of renal function. A study by Knauf et al. (1990) on the pharmacodynamic effect and pharmacokinetics of torasemide (20mg, single intravenous dose) in healthy controls and patients with stable CRF of varying degrees found the half-life of torasemide (3.4 to 4.1 hours) to be independent of renal func-tion. This was due to the fact that nonrenal clear-ance of torasemide was 3 times higher than its renal clearance.

In a controlled clinical trial, comparing the pharmacodynamics and pharmacokinetics of to-rasemide and furosemide in patients with high-grade renal failure after single intravenous doses of either torasemide 100 and 200mg or furosemide 100 and 200mg, all 4 drug preparations induced a significant increase in fractional as well as cumu-lative urine volume, sodium and chloride excre-tion during 24 hours. Sodium excretion was di-rectly correlated with the renal excretion of torasemide and furosemide (fig. 1). This has been noted as a general feature of loop diuretics (Brater et al. 1986, 1987; Knauf et al. 1990). In patients with renal failure, the half-life of torasemide in serum and urine was unchanged compared with healthy subjects, whereas it was prolonged in the case of furosemide (table I). As expected, renal clearance of both drugs was reduced in patients with renal failure, whereas total clearance of torasemide

be expected to exert any clinically relevant diuretic effects.

3. Clinical Efficacy of Loop Diuretics3.1 Acute Renal Failure

As previously discussed, there is no evidence in humans that loop diuretics prevent ARF. The out-come and prognosis of oliguric ARF are not influ-enced, but loop diuretics may improve the man-agement of these patients by increasing salt and water excretion. Furosemide (Brown et al. 1981; Cantarovich et al. 1973; Kleinknecht et al. 1976) and torasemide (Andreucci et al. 1990) were ad-ministered to patients with oliguric ARF. In these studies, high doses reversed oliguria into polyuria in most patients. Toxicity was dose related and appeared to be of concern at gram-doses of furo-semide. Side effects were not observed in patients on torasemide.

There is. increasing evidence for an important role of renal prostaglandins in various aspects of renal function. It has been shown, for example, that renal prostaglandin E excretion increases after intravenous administration of furosemide and to-rasemide (Dupont et al. 1988; Mackay et al. 1984). Kirsten et al. (1990) investigated the influence of piretanide (single intravenous dose) on vasoactive

prostagiandins, (catecholarnines,) renin and aldo-sterone in patients with ARF. It was shown that loop diuretics in high doses increased vasodilatory

prostaglandin levels in patients with ARF and that the increase was more pronounced in responders to loop diuretics than in nonresponders. By this mechanism, loop diuretics may counteract the vasoconstriction due to hyperactivity of the renin-angiotensin-aldosterone system in renal failure.

In conclusion, effective loop diuretic action seems to be dependent on a system which responds with an increase in vasodilatory prostaglandins. It could therefore be speculated that the effect of loop diuretics on intrarenal prostaglandins might con-tribute to their natriuretic effect.

3.2 Chronic Renal Failure

The efficacy of loop diuretics in CRF has been investigated in a number of controlled or compar-ative studies. The saluretic effect of torasemide was compared with furosemide in double-blind, con-trolled studies. Mourad et al. (1988) treated 46 patients with a GFR of < 30ml per minute. Torasemide 20mg had a short-lived natriuretic ef-fect, while torasemide l00mg and furosemide 60mg significantly increased 24-hour sodium excretion. Torasemide l00mg was more effective than furo-semide 60mg and had a longer duration of action. Calcium excretion was significantly increased only in the furosemide group (table II).

In a single dose multicentre study, intravenous torasemide 100 and 200mg was compared with the same doses of intravenous furosemide in 90 patients

Table II. Effect of torasemide 20mg and 100mg, furosemide (frusemide) 60mg and placebo after single intravenous (IV) doses on 24-

hour volume, sodium, potassium, chloride and calcium excretion in patients with chronic renal failure. Data are presented as a

mean percentage increase over the preceding control day (adapted from Mourad et al. 1988)

Change from control value (%)

no. of patients volume sodium potassium chloride calcium

Torasemide 20mg IV 11

Torasemide 100mg IV 10

Furosemide 60mg IV 13

Placebo 12

NS +34 NS +52 NS

+26 +78 NS +127 NS

+32 +55 NS +72 +40

NS NS NS NS NS

Abbreviation: NS = no significant change.

76 Drugs 41 (Suppl. 3) 1991

(creatinine clearance < 30 ml/24 hours) [Klusch et al. 1988; Risler et al. 1986]. Urine volume, and renal sodium, calcium and chloride excretion in-creased with both drugs. Potassium excretion was altered less by torasemide. A dose increase en-hanced the diuretic effect of both drugs. However, the increase in fractional excretion was greater with torasemide than with furosemide when the dose was doubled, indicating a steeper dose-response re-lationship for torasemide compared with furosem-ide in this dose range (fig. 2).

19 patients (creatinine clearance of 9 to 12ml per minute) who had previously been receiving fu-rosemide 500mg daily for 2 weeks, took part in a study which compared the effects of torasemide 100 and 200mg with those of furosemide 250mg, for 14 days (Kult et al. 1988). Compared with base-line on furosemide 500mg. water and sodium ex-cretion remained almost unchanged in the tora-semide 100mg group (volume: -7%. sodium: +12%) and decreased in the furosemide 150mg group (vol-ume: -11%, sodium: —15%), but increased signifi-cantly in the patients on torasemide 200mg (vol-ume: +20%, sodium: +47%). Another clinical trial compared high dose torasemide (200 mg/day orally) with furosemide (500 mg/day orally) in 10 patients with advanced CRF (Clasen et al. 1988). After 14 days the doses were doubled for a further 2 weeks of treatment Although torasemide was admini-stered in a 2.5 times lower dose, the effect of both drugs on oedema and fluid and sodium excretion was equipotent. Calcium excretion was signifi-cantly more pronounced in patients receiving fu-rosemide and plasma reran activity also increased in these patients but not in the torasemide--treated group. No adverse effects and, notably no impair-ment of cochlear function, were observed in either group, indicating that high dose torasemide is safe and effective in the treatment of advanced CRF.

Russo et al. (1990) investigated the efficacy of torasemide (200 mg/day) in 11 patients with hypertension and CRF. Torasemide significantly lowered blood pressure and reduced peripheral oedema in all patients without adverse effects (fig. 3).

3.2.1 HaemodialysisLoop diuretics have also been used to treat

patients on haemodialysis. Patients with a residual diuresis of 200 to 500ml benefit from diuretic therapy; their urinary output increases, and their fluid intake may be increased accordingly. The ad-vantages of this treatment are gains in patient com-fort and quality of life. Schulz et al. (1990) have compared the effect of torasemide 200mg with fu-rosemide 500mg and placebo in 80 patients over a 3-month treatment period. This randomised double-blihd trial demonstrated an increased ur-inary output of water, sodium and chloride in both actively treated groups compared with placebo. After 3 months, neurological examination dem-

Fig. 2. Median increases in 24-hour fractional excretion (FE), ∆ FE (obtained as median differences of FE in the therapy period, minus the preceding control period over 24 hours each) for volume, sodium and chloride after single intraven-ous doses of torasemide 100 and 200mg and furosemide 100 and 200mg (from Kult et al. 1990, .with permission). * = p 0.05 when comparing the 200mg to the l00mg dose.

Fig. 3. Reduction in blood pressure (bars) and bodyweight (line) in hypertensive patients with chronic renal failure during 9 days' treatment with intravenous torasemide (0.77 mg/kg bodyweight; from Russo et al. 1990, with permission). * .= p < 0.0025; ** = p < 0.0005.

onstrated 2 detericration of polyneuropathy (un-related to treatment in 4 furosemide patients. I on placebo and none on torasemide.

Similar results were demonstrated by Schmidt et al. (1981) in a short term study comparing fu-rosemide 240mg with the same dose of muzoli-mine. In a second study, the efficacy of different doses of torasemide and furosemide in 44 patients on haemodialysis were investigated (Stolear et al. 1990). Compared with pretreatment placebo con-trol, torasemide in doses of 100 to 200mg de-creased interdialytic weight gain and increased urine volume and sodium excretion simultaneously.

Haemodialysis and haemofiltration do not alter the pharmacokinetics of torasemide; as might be expected from its high degree of protein binding, it has been shown that no significant elimination of torasemide by dialysis occurs (Loute et al. 1986).

The administration of very high doses of these drugs in severs renal failure and on dialysis has provided a considerable amount of intermation on their toxicity. Furasumide is ototoxic in high doses. and toxicity is increased by aminoglycosides, Bu-metanide may provoke muscular discomfort in patients treated with more than 12mg per day. To date, there have been no reports of severe side ef-fects of torasemide or piretanide.

4. Conclusion

Torasemide is a high ceiling diuretic which, in comparison with furosemide, has a longer elim-ination half-life independent of renal function. To-rasemide increased fractional excretion of volume and sodium dose-dependently up to 200mg orally or intravenously in patients with CRF. Calcium

78 Drugs 41 (Suppl. 3) 1991

excretion appeared to be less than with furosemide. Torasemide was shown to be as effective as furo-semide in the diuretic management of patients with advanced renal failure, promoting diuresis and preventing weight gain without affecting the neu-rological status. Decreased GFR leads to retention and prolongation of the half-life of furosemide, which may account for an increase in therapeutic potency compared with torasemide. In patients with

normal renal function, the ratio of equipotency is1 : 2 (torasemide vs furosemide) and l : l in patients with severe renal failure after intravenous admin-istration. After oral administration, available data suggest an equipotency ratio of l : 2.5 (torasemide vs furosemide), whereas this ratio is approximately 1 : 4 in healthy volunteers and patients with normal renal function. The differences depending on route of administration reflect the almost complete bioavailability of torasemide compared with a bio-availability of approximately 50% for furosemide. In a study of Kampf and Baethke (1980), bume-tanide 6mg was less effective than furosemide 250mg in patients with a serum creatinine level be-tween 3 and 7 mg/dl. In another group of patients (serum creatinine between 7 and 14 mg/dl) bu-metanide 12mg had a smaller diuretic effect than furosemide 500mg.

In healthy humans, there is a ratio of 1: 40 be-tween responses to equal doses of bumetanide and furosemide. In renal failure this difference dimin-ishes to 1 : 11 (Kampf & Baethke 1930), with the maximal effect apparent - not at 1 to 1.5 hours -but at 6 hours.

In conclusion, torasemide is a new high ceilingloop diuretic which differs from other loop diuret-ics with respect to its almost complete bioavailability, its longer half-life and duration of action being independent of renal function, and its lack of severe side effects.

References

Allison MEM, Kennedy AC. Diuretics in chronic renal disease: a study of high dosage furosemide. Clinical Seience 41: 171-187, 1971

Andreasen. F. Hansen HE, Mikkelsen E. Phlarmacokinetics of furosemide in anephric patients and in normal subjects. European Journal of Clinical Pharmacology 13: 41-48. 1978

Andreucci NE. Russa D, Memoli B, Testa A. Rampino T, et al. Efficacy

of IV torasemide in the treatment of acute and chronic high grade renal failure. In Kruck et al. (Eds) Torasemide: Clinical Pharmacology and Therapeutic Applications, Progress, in Pharmacology and Clinical Pharmacology Vol. 8/1, pp. 229-238, Gustav Fischer Verlag, Stutt-gart, 1990

Baehler RW, Kotchen TA, Burke JA, Galla JH, Bhathena D. Considerations on the pathophysiology of mercuric chloride-induced renalfailure. Journal of Laboratory and Clinical Medicine 90: 330-340, 1971

Beall AC, Hall WC, Morris GC, DeBakey ME. Mannitol-induced osmotic diuresis during renal artery occlusion. Annals of Surgery 161:46-52, 1965 .

Beermann B, Groschinsky-Grind M. Clinical pharmacokinetics of diuretics. Clinical Pharmacokinetics 5: 221-245, 1980

Benet LZ. Pharmacokihetics/pharmacodynarnics of furosemide in man:a review. Journal of Pharmacokinetics and Biopharmaceutics 7: 1-27, 1979

Brater DC, Anderson SA, Brown-Cartwright D. Response to furosemide in chronic renal insufficiency: rationale for limited doses. Clinical Pharmacology and Therapy 40. 134-139, 1986

Brater DC, Leinfelder J, Anderson SA. Clinical pharmacology of tora-semide, a new loop diuretic. Clinical Pharmacology and Therapeutics 42: 187-192, 1987

Brezis M, Rosen S, Silva P, Epstein FH. Transport activity modifies thick ascending limb in the isolated perfused kidney. Kidney Inter-national 25: 65-72, 1984

Brown CB, Ogg CS, Cameron JS. High dose of furosemide in acute renalfailure: a controlled trial. Clinical Nephrology 15: 90-96, 1981

Cantarovich F, Galli C, Benedetti L, Chena C, Castro L, et al. High-dose furosemide in established acute renal failure. British Medical Journal 4: 449-450, 1973

Clasen W, Khartabil T, Imm S, Kindler J. Torasemide for diuretic treat-ment of advanced chronic renal failure. Arzheimittel-Forschung 38: 209-211, 1988

Cutler RE, Forrey AW, Christopher TG, Kimpel BM. Pharmacokinetics of furosemide in normal subjects and functionally anephric patients. Clinical Pharmacology and Therapeutics 15: 588-596, 1974

Delarge J. Chemistry and pharmacological properties of the pyridine-2-sulfonylurea derivative torasemide. Arzneimittel-Forschung 38: 144-150, 1988

De Torrente A, Miller PD, Cronin RE, Pauisin PE, Erickson AL, et alEffects of furosemide and acetylcholine in norepinephrine-inducedrenal failure. American Journal of Physiology 235: F131-F136, 1978

Dodion L, Willems JL. Study of the elimination kinetics of torasemide.a novel loop diuretic, in renal insufficiency. European Journal ofClinical Pharmacology 31 (Suppl.): 49-51, 1986

Dupont AG, Gerlo E, Van der Niepen P, Piepsz A. Renal pharmaco-dynamic effects of torasemide and furosemide in normal man Arz-neimittet-Forschung 38: 172 175, 1988

Epstein M, Schneider NS, Befeler B. Effect of intrarenal furosemide onrenal function and intrarenal hemodynamics in acute renal failure.American Journal of Medicine 58: 510-516, 1975

Fink M. Are diuretics useful in the treatment of prevention of acute renalfailure? Southern Medical Journal 75: 329-334, 1982

Flamenbaun W, Friedman R. Pharmacology, therapeutic efficacy, are adverse effects of bumetanide, a new 'loop' diureutic. Pharmacother apy 2: 213-222, 1982

Fritz K.W, Wilbrandt R, Piehl W, Freyland MD, Freund HW. Long-term high dosage furosemide in chronic renal insufficiency. Post-graduate Medicine 47: 4244, 1971

Goto S, Yoshitomi H, Miyamoto A, [none K, Nakano M. Binding of several loop diuretics to serum albumin and human serum from patients with renal failure and liver disease. Journal of Pharmaco-dynamics 3: 667-676, 1980

Grabensee B, Knabe P, Koczy B, Hecring P, Achhammer J, et al. Wit-kungsvergleich unterschiedlicher oraler Dosen von Torasemid and Furosemid bei chronischer Niercninsuffizienz. Nieren and Hoch-druckkrankheiten 15: 374, 1986

Greger R, Schlatler E. Cellular mechanism of the action of loop diuretic on Ihe thick ascending limb of Henle's loop. Klinische Woc-henschrifl 61: 1019-1027, 1983

Hanley MJ, Davidson K. Prior mannitol and furosemide infusion in a

model of ischemie acute renal failure. American Journal of Physiol-ogy 241: F556-F564. 1981

Higashio T. Abe Y, Yamamote K. Renal effects of bumetanide. Journal of Pharmacology and Experimental Therapeutics 207: 212-220. 1978

Holazo AA, Colburn WA. Gustafson JH, Young RL. Parsonnet M. Phar-macokinetics of bumetanide following intravenous, intramuscular, and oral administrations to normal objects. Journal of Pharmaceutical Sciences 73: 1108-1113, 1984

Huang CM, Atkinson A. Levin N, Quintanilla A. Pharmacokinetics of furosemide in advanced renal failure. Clinical Pharmacology and Therapeutics 16: 659-666, 1974

Kampf D, Baethke R. Die diuretische Effektivitat von Bumetanid im kontrollierten Vergleich zu Furosemid bei chronischer Niereninsuf-fizienz unterschiedlichen Schveregrades. Arzneimittel-Forschung 30: 1015-1018, 1980

Keller E, Hoppe-Seyler G, Mumm R, Schollmeyer P. Influence of he-patic cirrhosis and end-stage renal disease on pharmacokinctics and pharmacodynamics of furosemide. European Journal of Clinical Pharmacology 20: 27-33, 1981

Kirsten R, Rictbrock I, Huber ED. Heintz B. Nelson K, et al. Influence of piretanide on vasoactive prostaglandins, catecholamines, renin and aldosicrone in patients with acute renal failure. In Puschctt & Green-berg (Eds) Diuretics III: chemistry, pharmacology and clinical appli-cations. Elscvicr Scicnt Publishing Company. New York. 1990

Kleinknecht D, Ganeval D, Gonzalez-Duque LA, Fermanian J. Furosemide in acute oligutic renal failure: a controlled trial. Nephron 17: 51-58, 1976

Klutsch K., Grosswendt J, Haecker W. Single dose comparison of torasemide and furosemide in patients with advanced renal-failure, Arzneimittel-Forschung 38: 200-204, 1988

Knauf H, Spahn H, Rucker II-M, Mutschler E. The loop diuretic torasemide in renal failure. Kinetics and dynamics. In Kruck

et. al. (Eds) Torasemide: Clinical Pharmacology and Therapeu-tic Applications. Progress in Pharmacology and Clinicalpharmacology vol. 84 no.81,93. Gustav Fisher Verlag, Stutigart. 1990

Kramer BK. Risier T Xipamide- Cardiovascular Drug Review, 6: 141-154, 1988

Kult J, Hacker W, Glocke M. Comparison of efficacy and tol-erance of different oral doses of torasemide and furosemide in patients with advanced chronic renal failure. Arzneimittel-For-schung 38: 212-214. 1988

Kult J, Ziegler J, von Mollendorf E. Pharmacodynamics and pharmacokinetics of torasemide and furosemide in patients with high grade renal failure after application of high intravenous doses. In Kruck et al. (Eds) Torasemide: Clinical Pharmacol-ogy and Therapeutic Applications. Progress in Pharmacology and Clinical Pharmacology Vol. 8/1, pp. 239-248, Gustav Fischer Verlag, Stuttgart, 1990

Lau HSH, Heyneck ML, Berardi RR, Swartz RD, Smith DE. Ki-netics, dynamics, and bioavailability of bumetanide in healthy subjects and patients with chronic renal failure. Clinical Pharmacology and Therapeutics 39: 635-645, 1986

Lesne M. Comparison of the pharmacokinetics and pharmaco-dynamics of torasemide and furosemide in healthy volunteers. Arzneimittel-Forschung 38: 160-163, 1988

Levine SD. Diuretics. Medical Clinics of North America 73: 271-282, 1989

Loute G, Adam A, Ers P, Heremans C, Willems B. The influence of haemodialysis and haemofiltration on the clearance of to-rasemide in renal failure. European Journal of Clinical Pharmacology 31 (Suppl.): 53-55, 1986

Mackay IG, Muir AL, Watson ML. Contribution of prostaglan-dins to the systemic and renal vascular response to furosemide in normal man. British Journal of Clinical Pharmacology 17: 513-519, 1984

Maharaj B. Diuretics in retinal failure. Progress in Pharmacology 6: 267-288, 1988Marcantonio LA, Auld WKR, Murdoch WR, Purohit R, Skellern

GG, et al. The pharmacokinetics and pharmacodynamics of

the diuretic bumetanide in hepatic and renal disease. British Journal of Clinical Pharmacology 15: 245-252. 1983

Marone C. Reuhi FC. Perisic M. Lahn W. Pharmacokinctics of high closes of piretanidc in moderate to severe renal failure. European Journal of Clinical Pharmacology 27: 589-593. 1984

Minuth AN, Terrell JB, Suki WN. Acute renal failure: a study of the course and prognosis of 104 patients and of the role of furosemide. American Journal of Medical Sciences 271: 317-324, 1976

Mourad G. Haecker W, Mion C. Dose-dependent salidiuretic ef-ficacy of torasemide in comparison to furosemide and placebo in advanced renal failure. Arzneimittel-Forschung 38: 205-208. 1988

Neugebauer G. Besenfelder E, von Mollendorff E pharmacoki-netics and metabolism of torasemide in man Arzneimittel-Forschung 38:164-166: 1988

Oberleithner H. Giebisch G, Lang F. Wang W. Cellular mech-anism of the furosemide sensitive transport system in the kid-ney. Klinische Wochenzeitschrift 60: 1173-1179. 1982

Pentikaainen PJ. Pasternack A. Lampainen E. Neuvonen PJ. Penttila A. Bumetanide kinetics in renal failure. Clinical Pharmacology and Therapeutics 37: 582-588. 1985

Rane A. Villeneuve JP, Stone WJ, Nies AS. Wilkinson GR, et al. Plasma binding and disposition cf furosemide in the nephrotic syndrome and in uremia. Clinical Pharmacology and Thera-peutics 24: 199-207, 1978

Risler T. Hellstern R, Ress K. Achhammer A, Hacker W. et al. Torasemid bei chronischer Niereninsuffizienz. Nieren- und Hochdruckkrankheiten 15: 527-528. 1986

Rodrigo F. Shideman J. McHugh R. Buselmeier T. Kjellstrand C. National history, clinical correlations and influence of di-alysate glucose and intravenous mannitol. Annals of Internal Medicine 86: 554-561, 1977

Russo D. Gazzotti MR, Testa A. Torasemide a new loop diuretic in patients with chronic renal failure. Nephron 55: l41-145. 1990

Schmidt P. Loew D, Dycka J. Kopsa H. Baleke P. et al. Com-purison of the effects of neurochronic and furosemide in patients with and-stage renal failure and chronic dialysis. European, Journal of Chinical Pharmacology 20: 23-26,1981

Schulz. W, Dorfler A. Stiehl L. Achhammer I. Double blind chinical trial investigating the efficacy and long-term tolerance of torasemide 200mg p.o. compared with furosemide 500mg p.O. and placebo p.o. in patients with chronic renal failure on hemodialysis - a multicenter study. In Kruck et al. (Eds) Tora-semide Clinical Pharmacology and Therapeutic Applications. Progress in Pharmacology and Clinical Pharmacology, Vol. 8/ 1, pp. 249-257. Gustav Fischer Verlag, Stuttgart. 1990

Stolear IC, Achhammer I, Georges B. Efficacy of torasemide in the treatment of patients with high-grade renal failure on di-alysis. Progress in Pharmacology and Clinical Pharmacology Vol. 8/l, pp. 259-267. Gustav Fischer Verlag, Stuttgart. 1990

Stroobandt R. Dodion L, Kaesteloot H..Clinical efficacy of to-rasemide, a new direutic agent, in patients with acute heart failure: a double blind comparison with furosemide Archives of International Pharmacodynamics 260: 151-15S. 1982

Tiller DJ, Mudgc GH. Pharmacologic agents used in the man-agement of acute renal failure. Kidney International 18: 700-7 l l , 1980

Tilstone WJ. Fine A. Furosemide kinetics in renal failure. Clinical Pharmacology and Therapeutics 23: 644-650. 1978

Walter U, Rockel A, Lahn W, Heidland A. Heptner W. Phar-macokinctics of the loop diuretic piretanide in renal failure. European Journal of Clinical Pharmacology 29: 357-343. l985

Wollam GL. Tarazi RC, Bravo EL. Dustan HP. Diuretic potency of combined hydrochlorothiazide and furosemide therapy in patients with azotemia. American Journal of Medicine 72: 929-938, 1982

Correspondence and reprints: Dr Teut Risler, Section of Nephrol-ogy and Hypertension, Department of Medicine III, University of Tubingen, Otfried-Muller-Strasse 10, 74 Tubingen, Federal Re-public of Germany.

the efficacy of diuretics in acute and chronic renal failure

Documents