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Eur J Clin Pharmacol (2009) 65:465–472DOI 10.1007/s00228-009-0626-7 Torasemide significantly reduces thiazide-induced potassiumand magnesium loss despite supra-additive natriuresis H. Knauf & E. Mutschler & H. Velazquez & G. Giebisch Received: 12 November 2008 / Accepted: 23 January 2009 / Published online: 20 February 2009 # The Author(s) 2009. This article is published with open access at combination significantly reduced K+ and Mg2+ excretion.
Background Resistance to high-dose loop diuretics can be The K+-sparing effect of the HCT/TO combination was overcome either by co-administration with thiazides or by shown to be due to a significant reduction in the HCT- treatment with medium-dose loop diuretics combined with induced increase in fractional K+ excretion by the loop thiazides. Combination therapy has been proven to be diuretic. Total excretion of Ca2+ relative to Na+ excretion superior to high-dose loop diuretic monotherapy for cardiac was less with the HCT/TO combination than with TO given and renal edema. However, such a strongly efficacious short-term regimen is often complicated by undesired Conclusion The enhancement of desired NaCl excretion by effects, including circulatory collapse and electrolyte the HCT/TO combination with significant reduction of disturbances. The question of whether the loop diuretic/ undesired loss of K+ and Mg2+ meets clinical requirements thiazide combinations are efficacious and safe when but has to be validated in long-term clinical trials.
conventional doses are combined has not yet beenanswered.
Keywords Hydrochlorothiazide . Torasemide .
Methods The effects of hydrochlorothiazide (HCT) and Combination therapy . Supra-additive natriuresis .
torasemide (TO) given alone on the excretion of Na+, Cl-, K+, Mg2+, and Ca2+ were compared with the effects ofcombined administration of the diuretics in 12 healthyvolunteers.
Results The co-administration of HCT (25 mg) with TO (5or 10 mg) strongly increased Na+ excretion. However, the High-dose monotherapy with loop diuretics has suc-cessfully been replaced by the administration ofmedium-dose loop diuretics combined with thiazides H. Knauf (*)Department of Medicine 1, St. Bernward-Krankenhaus, in patients with chronic edema and chronic renal failure ]. Such combinations of diuretics, each acting on different segments of the nephron—known as “sequen-tial nephron blockade Pharmacological Institute, University of Frankfurt/Main, uretics in edematous states [–Although this physiologically grounded rationale is more effectivethan high-dose monotherapy when a rapid and robust diuretic response is needed, such treatment may lead to Research Office, VA Healthcare System,West Haven, CT 06516, USA complications such as fluid and electrolyte disturbances, ].
Conventional-dose combinations of loop diuretics (e.g., Department of Cellular & Molecular Physiology, 5 or 10 mg torasemide) and thiazides (e.g., 25 mg Yale University, School of Medicine,New Haven, CT 06520, USA hydrochlorothiazide) have so far not been introduced in clinical practice for the long-term treatment of hypertension or chronic heart failure. This is obviously due to the clinicalexperience that high-dose loop/thiazide diuretic combina- As a representative thiazide, hydrochlorothiazide (HCT, tions cause electrolyte disturbances.
HEXAL Pharmaceuticals), 25 mg, was used in the study In the present study, we examined conventional dose since it has been available for long time and the greatest combinations of loop diuretics and thiazides in healthy body of evidence and experience has been accumulated for volunteers free of any patient bias with particular focus on it [Torasemide (TO, HEXAL Pharmaceuticals), 5 or the relationship between sodium, potassium, and magne- 10 mg, is a “newer” loop diuretic of the furosemide-type with a longer duration of action and a significantly higherbioavailability []. The diuretics were given alone andin combination. All diuretics were given orally in a single dose under clinical control of the monitor of the trial.
The ethically approved trial (University of Göttingen, Germany) was performed on 12 healthy volunteers (28–48 years old, 6 male, 6 female), who had given their In accordance with earlier studies , ], urine was written informed consent to the study. Prior to adminis- collected after drug administration (8 A.M.) in the hospital tration of a drug, they underwent a clinical check-up for a 24-h period, divided into two 3-h collections, one including kidney, liver, and hematological tests, and 6-h collection, and one 12-h collection. Baseline (control) ECG. The participants were free of any medication.
collections were obtained from 24 to 0 h prior to drug They were kept on a standard diet, receiving a defined administration using the same intervals (i.e., −24, −21, −18, fluid (1.5 l/day) and salt intake (100 mmole Na+ and 80 −12, 0 h). An aliquot of the defined volume of the mmole K+ per day) 3 days before and throughout the respective collection period was frozen until analyzed for study. At least 1 week wash-out period was introduced Na+, Cl−, K+, Mg2+, Ca2+, and creatinine using a MODULAR Analyzer (Roche, Switzerland). For monitor- Total Excretion
5 or 10 mg, with hydrochlorothi-azide (HCT), 25 mg, on totalexcretion of Na+ (upper panel)and on the excretion of K+ and Mg2+ (lower panel) as comparedto HCT alone. The left barpresents the data for 0–12 h, the right bar for 0–24 hcollection periods. The data aremeans ± SE for 12 healthy volunteers. For controls, furtherexcretion data, and statistical Dose [mg]
ing the glomerular filtration rate (GFR) and the fractional were taken prior to the study as well as 3, 6, 12, and 24 h excreted in the urine relative to the amount filtered (GFR × First, total excretion of volume and electrolytes was determined from urine collected in the respective periods.
Then net excretion induced by a diuretic regimen was calculated for each participant from total excretion minus baseline (control) obtained in the respective pretreatment period. Thus, each run or experimental series was compared with its own control 24 h prior to drug administration.
Administration of the diuretics alone and the diuretic combination was performed in a randomized design. All data are expressed as mean values ± SE. Statistical evaluation was performed using analysis of variance adjusted for multiple testing. Statistical significance was Figure illustrates total excretion rates of Na+, K+, and Mg2+ obtained in 0- to 12-h and 0- to 24-h collection periods. Hydrochlorothiazide (HCT, 25 mg) induced a strong natriuresis for 12 h, consistent with the time of action of this diuretic. The addition of the loop diuretic TO, 5 or 10 mg, to HCT strongly increased Na+ excretion in a dose-dependent manner. With respect to a once-a-day drug administration, which includes the postdiuretic period (12– 24 h), the co-administration of HCT with TO increased total Na+ excretion without being curtailed by postdiuretic Na+ Strikingly, K+ excretion did not increase in proportion to Na+ excretion. Rather, K+ excretion declined with increas- ing doses of TO co-administered with the thiazide. HCT- induced excretion of Mg2+ was also reduced by increasingdoses of TO. These findings were then analyzed in detail by a statistical evaluation of the excretion data given in Compared to controls, HCT induced strong Na+ and Cl− excretion. Positive NaCl excretion was maintained up to 24 h after drug administration. TO, however, induced significant Na+ excretion only for 0–12 h. In terms of mmoles, the HCT-induced excretion of K+ was about 40% that of Na+. TO, however, was significantly less kaliuretic than HCT. The loop diuretic did not increase K+ excretion above control for the 0- to 12-h or 0- to 24-h periods.
Diuretic-induced excretion of Mg2+ very much paralleled that of K+: HCT induced strong Mg2+ loss for 0–12 and bar presenting the net natriuretic effect induced by 0–24 h as well, whereas TO did not significantly change combined administration of HCT and TO. The time course total Mg2+ excretion compared to controls.Concerning Ca2+ in Fig. shows that the net diuretic effect of the loop excretion, there was no Ca2+ loss during the 0- to 12-h and diuretic TO given alone was positive only for 6 h (periods 0- to 24-h periods with HCT, whereas the loop diuretic 0–3 and 3–6 h). Throughout the remainder of the study significantly increased Ca2+ excretion above control for the period (6–12 h, 12–24 h), net sodium excretion became negative. After approximately 6 h, significant NaCl A comparison of combined administration of HCT and retention occurred resulting in a “rebound effect” (Na+ TO versus HCT given alone shows that the combination is excretion below baseline) that diminished the overall a significantly stronger natriuretic regimen than HCT, both natriuretic effect. In contrast, the thiazide diuretic acted for the 0- to 12-h and the 0- to 24-h period. Total excretion for approximately 12 h and lacked a significant rebound of K+ relative to Na+ during 0–24 h was only 20% as effect. The rebound seen with TO given alone is effectively compared to 40% with HCT given alone. Also Mg2+ reduced by co-administered HCT. Figure illustrates that excretion was significantly reduced by the HCT/TO combined administration of conventional doses of HCT and combination as compared to HCT given alone. Ca2+ TO is by far a stronger natriuretic regimen (“supra- excretion obtained by the HCT/TO combination was greater additive”) than when the components are given separately.
than that with HCT given alone only for 0–12 h. On the The diuretic-induced net excretion of K+ and Mg2+ is other hand, a comparison of the HCT/TO combination with illustrated in Fig. . After 12 h, combined administration of TO given alone shows that total Ca2+ excretion induced by 25 mg HCT with 10 mg TO induced a net K+ excretion of the combination did not differ significantly from that only about half the amount obtained by the individual obtained with the loop diuretic given alone, although the components given separately. The attenuation of HCT- HCT/TO combination was by far a stronger natriuretic induced K+ loss by TO is also clearly demonstrated for the regimen. Stated differently, total excretion of Ca2+ relative 0- to 24-h period: K+ loss following separate administration to Na+ excretion with the HCT/TO combination equalled of HCT and TO combined in the left bar was lowered to that with HCT given alone, but was less than that obtained about one-third by combined administration of HCT and by the loop diuretic given alone. Table also includes the TO (right bar). The same effects held true for net Mg2+ HCT-induced transient fall in GFR (4–6 h after medica- excretion both for the 0- to 12-h and the 0- to 24-h period.
tion). This phenomenon was absent in the presence of TO,in agreement with earlier reports [ Net Na+ Excretion
Urinary excretion following drug administration is a complex process as the drug effect is superimposed upon or mixed with the baseline excretion of the kidney. Therefore, we focused on the drug effect per se by calculating “net excretion” rates free of the baseline excretion. Net excretion was determined for each individual by taking into account the baseline excretion in the respective pretreatment period (see Table ). The net natriuretic effect obtained by combined administration of HCT (25 mg) and TO(10 mg) was always significantly greater than the sum of the net effects obtained by the components given alone.
This “supra-additive” natriuretic effect of the thiazide/loopdiuretic combination in healthy young volunteers exceeds the sum of the individual effects by a factor of 1.3. It should Collection Period Following Drug Administration [h]
be noted (not given in Table ) that the lower-dosecombinations of HCT (25 mg)/TO (5 mg) and HCT Fig. 2 Effect of HCT, 25 mg, and TO, 10 mg, and the combination (12.5 mg)/TO (5 mg) also resulted in a significant increase of both diuretics on “net excretion” of Na+. The data are plotted fordistinct collection periods to illustrate the time courses of the different in natriuresis of 30%. This phenomenon is in agreement regimens. Net excretion was calculated as total excretion minus the with earlier observations in edematous patients (see the respective pretreatment baseline excretion in each individual for each regimen. The effects of the components alone are combined In Fig. the natriuretic net effects of HCT (25 mg) and in the left bar to compare with the effect obtained by combinedadministration in the right bar. Negative excretion (e.g., with TO TO (10 mg) are plotted for the distinct collection periods.
from 6–24 h) denotes less natriuresis than baseline excretion The net effects of HCT and TO given separately are (“rebound”). Effect of combined administration vs the sum of the combined in a single bar to be matched against the second Net K+ Excretion
period, the FEK of the HCT-containing regimen was still slightly above baseline. Neither changes in blood chemistry nor adverse drug reactions were observed throughout the The present experiments have shown that the co- administration of conventional and lower doses of loopand thiazide diuretics yielded a net diuretic/natriuretic effect that was significantly greater than the sum of the net individual effects of each class of diuretic. This finding is in accordance with earlier observations first made in patientswith fluid retention (see the “” section). The Net Mg2+ Excret ion
gain in natriuretic efficacy of about 30% in healthy young volunteers needs further consideration. The addition of a loop diuretic to a thiazide may enhance NaCl excretion byseveral mechanisms, none of which are mutually exclusive.
Loop diuretics do not appear to potentiate the effect of athiazide by altering their pharmacokinetics or bioavailabil- ity [–Rather, pharmacodynamic mechanisms seem toplay the predominant role in diuretic-induced electrolyte Given the axial organization of transport mechanisms in the different segments of the nephron and the segment- specific inhibition of salt transport by diuretics, the result of treatment is the sum of all direct and indirect effects on Collection Period Following Drug Administration
solute transport along the nephron. For example, whenNaCl reabsorption along the thick ascending limb of Fig. 3 Effect of HCT, 25 mg, and TO, 10 mg, alone, and thecombination of both diuretics on net excretion of K+ (upper panel) Henle’s loop (TALH) is inhibited by loop diuretics, the and Mg2+ (lower panel) plotted in paired bars (means ± SE). As in NaCl concentration in the fluid that enters the distal tubule Fig. the effects of the diuretics HCT and TO given alone arecombined in the left bar to compare with combined administration inthe right bar. Data are cumulative for 0- to 12-h and 0- to 24- Fractional K+ Excretion
h collection periods (see Table data in parenthesis). Effect of combined administration vs the sum of the single effects: *P<0.05 It should be mentioned that the significant attenuation of K+ and Mg2+ excretion was also obtained by the lower dosecombinations of HCT and TO.
To focus on renal handling of potassium filtration and excretion, the fractional K+ excretion was studied in the presence of conventional doses of the thiazide and the loop diuretic given alone and in combination. As illustrated in Fig. the FEK following the administration of 25 mg HCTsignificantly increased during the 0- to 3-h period and most evidently during the 3- to 6-h period to more than three 12–24 h
Collection Period Following Drug Administration [h]
times baseline FEK of 0.1 on average. However, the loopdiuretic TO, 10 mg, did not significantly increase FEK Fig. 4 Effect of HCT, 25 mg, and TO, 10 mg, alone, and the during these periods. Strikingly, the loop diuretic co- combination HCT/TO on fractional K+ excretion (K+ excreted administered with the thiazide significantly reduced the relative to K+ filtered) plotted for distinct collection periods. Forcomparison, control FE K is also given. The results are means ± SE for 12 healthy volunteers. HCT or TO vs control: *P<0.05, HCT+TO vs the thiazide, as also illustrated in Fig. In the postdiuretic is greatly increased. In a microperfusion study in rats ], In long-term treatment with loop diuretics, “diuretic Na+ absorption rose by a factor of three under those adaptation” ] develops associated with epithelial hyper- conditions. As a consequence, the apparent inhibition of trophy and hyperplasia, including the activation of Na+/K+- NaCl reabsorption in the loop of Henle is attenuated by ATPase , ]. The administration of thiazides prevented increased tubular reabsorption in more distal nephron sites.
the activation of distal tubular Na+/K+-ATPase ]. It was This increase in sodium reabsorption can be blocked by also shown in humans ] that chronic treatment with loop luminal thiazide acting on the early distal tubule. Hence, the diuretics enhanced ion transport in the distal tubule. These net effect of acute loop-diuretic administration on urinary data once again support the rationale for the combined NaCl excretion reflects the sum of effects in the diuretic- administration of loop diuretics with thiazides to counter- sensitive segment (e.g., inhibition of Na+/K+/2Cl− transport balance the process of diuretic adaptation.
in the TALH) and in the loop diuretic-insensitive segments The finding of lowered excretion of K+ and Mg2+ (secondary stimulation of NaCl reabsorption in the down- despite the strong natriuretic efficacy of the HCT/TO combination is novel and was unexpected. However, in a The combination of thiazides with loop diuretics prevents previous microperfusion study in rats ], it was shown not only the stimulating effect of luminal Na+ concentration that thiazides such as HCT or tizolemide increase distal on NaCl uptake in the early distal tubule, but the thiazides tubular potassium secretion yielding a higher K+ excretion also inhibit carbonic anhydratase (CA) in the proximal than in controls. Yet these kaliuretic agents failed to tubule, thereby increasing Na+ delivery to the TALH [ enhance distal potassium secretion when given together –This is due to the fact that thiazides retain a with furosemide or piretanide. The inhibition of the sulfamyl side group on the benzene ring characteristic of a thiazide-induced increase in distal tubular K+ secretion CA inhibitor such as acetazolamide ]. Thus, thiazides play a dual role: they block the Na+/Cl− co-transport in the Insights gained from more recent experiments now early distal tubule and also—to varying extents—the proxi- permit a tentative explanation of the potassium-sparing mal tubular CA. The order of potency for carbonic anhydratase effect of low-dose diuretic combinations used in this trial.
inhibition is chlorthalidone > benzthiazide > polythiazide > Potassium is filtered by the glomeruli, and most of the chlorothiazide > bemetizide > hydrochlorothiazide > xipamide potassium filtered is reabsorbed from the lumen by the time fluid emerges from the thick ascending limb of Henle’s In addition, loop diuretics also have a dual effect: first, they loop and enters the distal tubule. Potassium excreted in the block Na+/K+/Cl− transport in the TALH, and in addition, final urine (equal to approximately 10% of the amount they increase Ca2+ delivery to the distal tubule [], which filtered) largely represents the amount secreted by the cells decreases apical Na+ conductivity of the principal cells ].
of the connecting tubule and collecting duct. Potassium Thus, some further Na+ inhibitory effect—as is known to secretion occurs through potassium channels, but this occur with sodium channel blockers—contributes to the process also depends on the presence of luminal membrane supra-additive effect obtained with the combination HCT/TO.
sodium channels in the apical membrane of principal cells.
Taken together, the HCT/TO combination inhibits NaCl The co-existence of these two channels generates the reabsorption at four sites of the nephron: in the proximal electrical driving force for potassium secretion Block- tubule (HCT), in the loop of Henle (TO), in the early distal ing sodium channels with K+-sparing diuretics such as tubule (HCT), and in the late distal tubule (TO). This mode amiloride, for example, decreases the driving force for of action along the nephron corresponds to “sequential potassium secretion in the distal tubule. Other agents also have been shown to block the sodium channels of the distal Thiazide monotherapy may—at least in short-term tubule For example, increases in luminal Ca2+ treatment—be curtailed by a transient fall in GFR and a concentration in the range normally present in the distal consequent reduction in Na+ excretion Through the tubule reduce net K+ secretion by decreasing the electro- co-administration of TO, known to block tubuloglomerular chemical driving force for K+ secretion. These data may feedback [, ], these effects could be prevented.
be relevant to the present study and may help to explain Postdiuretic NaCl retention (“rebound”) is known to be the potassium-sparing effects of combined HCT/TO more prominent the greater the peak natriuresis and the shorter the duration of the diuretic’s action and is observed In rat microperfusion experiments [it was shown with loop diuretics ]. The net effect of a strong but short- that the ability of Na+ channel blockers such as amiloride to acting loop diuretic may therefore approach zero for a inhibit distal tubular K+ secretion and Na+ reabsorption 24-h period. However, when combined with thiazides, the requires the presence of luminal Ca2+. Since thiazides natriuretic efficacy of loop diuretics can be improved and stimulate Ca2+ reabsorption by the distal tubule ] and thus reduce the luminal Ca2+ concentration, thiazides alone might be expected to increase potassium excretion. Loop The generous support of the trial by HEXAL, Holzkirchen, Germany, is greatly appreciated.
diuretics, on the other hand, when co-administered withthiazides might reduce K+ excretion by increasing distal The authors have no conflict of interest to disclose.
tubular Ca2+ concentration, inhibiting the sodium channel,and decreasing the driving force for K+ secretion. Thus, the This article is distributed under the terms of the loop diuretic/thiazide combination may show a stronger Creative Commons Attribution Noncommercial License which per-mits any noncommercial use, distribution, and reproduction in any antikaliuretic effect relative to Na+ excretion than the medium, provided the original author(s) and source are credited.
antikaliuretic agent/thiazide combination. Therefore, TOmay have a dual effect in the nephron: it directly blocks theNa+:K+:Cl− carrier in the TALH and, in addition, it couldaffect distal tubular K+ secretion by increasing Ca2+ Given an equivalent natriuresis and diuresis, torasemide was shown to be less kaliuretic than furosemide [].
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