Torasemide Significantly Reduces Thiazide-Induced Potassium and Magnesium Loss Despite Supra-Additive Natriuresis

View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector Eur J Clin Pharmacol (2009) 65:465–472 DOI 10.1007/s00228-009-0626-7 PHARMACODYNAMICS Torasemide significantly reduces thiazide-induced potassium and 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 Springerlink.com Abstract 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 alone. 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 been answered. 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-, Potassium and magnesium sparing effects K+,Mg2+, and Ca2+ were compared with the effects of combined administration of the diuretics in 12 healthy volunteers. Introduction Results The co-administration of HCT (25 mg) with TO (5 or 10 mg) strongly increased Na+ excretion. However, the High-dose monotherapy with loop diuretics has suc- cessfully been replaced by the administration of H. Knauf (*) medium-dose loop diuretics combined with thiazides Department of Medicine 1, St. Bernward-Krankenhaus, in patients with chronic edema and chronic renal failure 31134 Hildesheim, Germany [1–12]. Such combinations of diuretics, each acting on e-mail: [email protected] different segments of the nephron—known as “sequen- ”— E. Mutschler tial nephron blockade break the resistance to di- Pharmacological Institute, University of Frankfurt/Main, uretics in edematous states [13–27]. Although this Frankfurt am Main, Germany physiologically grounded rationale is more effective than high-dose monotherapy when a rapid and robust H. Velazquez Research Office, VA Healthcare System, diuretic response is needed, such treatment may lead to West Haven, CT 06516, USA complications such as fluid and electrolyte disturbances [13, 28, 29]. G. Giebisch Conventional-dose combinations of loop diuretics (e.g., Department of Cellular & Molecular Physiology, Yale University, School of Medicine, 5 or 10 mg torasemide) and thiazides (e.g., 25 mg New Haven, CT 06520, USA hydrochlorothiazide) have so far not been introduced in 466 Eur J Clin Pharmacol (2009) 65:465–472 clinical practice for the long-term treatment of hypertension Diuretics used or chronic heart failure. This is obviously due to the clinical experience 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 [30]. Torasemide (TO, HEXAL Pharmaceuticals), 5 or the relationship between sodium, potassium, and magne- 10 mg, is a “newer” loop diuretic of the furosemide-type sium excretion. with a longer duration of action and a significantly higher bioavailability [31, 32]. The diuretics were given alone and in combination. All diuretics were given orally in a single Methods dose under clinical control of the monitor of the trial. The ethically approved trial (University of Göttingen, Study protocol and analysis Germany) was performed on 12 healthy volunteers (28– 48 years old, 6 male, 6 female), who had given their In accordance with earlier studies [32, 33], 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.Theparticipantswerefreeofanymedication. 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 between series. MODULAR Analyzer (Roche, Switzerland). For monitor- Fig. 1 Effect of co-administered Total Excretion + loop diuretic torasemide (TO), [mmole] Na 5 or 10 mg, with hydrochlorothi- 400 azide (HCT), 25 mg, on total excretion of Na+ (upper panel) + and on the excretion of K and 300 Mg2+ (lower panel) as compared to HCT alone. The left bar – presents the data for 0 12 h, 200 the right bar for 0–24 h collection periods. The data are means ± SE for 12 healthy volunteers. For controls, further 100 excretion data, and statistical 0 – 12 h analysis, see Table 1 0 – 24 h 0 [mmole] K+ 150 Mg2+ 100 50 0 – 12 h 0 – 24 h 0 HCT 25 25 25 TO - 5 10 Dose [mg] Eur J Clin Pharmacol (2009) 65:465–472 467 ing the glomerular filtration rate (GFR) and the fractional + + excretion of K ,FEK, plasma creatinine, and plasma K were taken prior to the study as well as 3, 6, 12, and 24 h + after drug administration. FEK represents the amount of K excreted in the urine relative to the amount filtered (GFR × + plasma K ). (HCT+TO) vs TO. All First, total excretion of volume and electrolytes was c 6h 12h 24h 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 GFR (ml/min) 0h 4 (HCT+TO) vs HCT, with its own control 24 h prior to drug administration. b Statistical analysis 2+ Ca 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 accepted when P<0.05. 2+ Mg HCT or TO or (HCT+TO) vs control, a Results Figure 1 illustrates total excretion rates of Na+,K+, and 2+ Mg obtained in 0- to 12-h and 0- to 24-h collection + periods. Hydrochlorothiazide (HCT, 25 mg) induced a K 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 Cl 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+ in each experimental condition refers to the 0- to 12-h collection period, the second to the 0- to 24-h collection period. Controls are retention. + Strikingly, K excretion did not increase in proportion to irst row + + + Na excretion. Rather, K excretion declined with increas- rates calculated for each individual from total excretion minus the respective pretreatment baseline excretion. These net excretion data slightly ” ing doses of TO co-administered with the thiazide. HCT- Na induced excretion of Mg2+ was also reduced by increasing doses of TO. These findings were then analyzed in detail by a statistical evaluation of the excretion data given in net excretion “ Table 1. 1,045±982,425±216a 147±152,015±197a 235±21a (93±11)2,902±137ac 190±19 (53±6) 349±21abc 233±23a (194±20) 123±12 350±23abc 187±20a 102±7a (47±5) 55±5 77±5abc (15±2) 59±6 (4±1) 21.0±4.0a (12.7±2.0) 11.0±1.2b (2.8±0.3) 2.6±0.3 8.7±0.9 (0.4±0.1) 3.7±0.4 8.3±0.8 3.9±0.5 3.2±0.4 (ml/12h) (mmol/12h) Compared to controls, HCT induced strong Na+ and Cl− (ml/24h) (mmol/24h) excretion. Positive NaCl excretion was maintained up to 24 h after drug administration. TO, however, induced denote the 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 in parenthesis than HCT. The loop diuretic did not increase K+ excretion Summary of urinary excretion data and glomerular filtration rate (GFR) above control for the 0- to 12-h or 0- to 24-h periods.

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