[Metolazone in arterial hypertension. Multi-centric study with 2.5 mg of Zaroxolyne (metolazone) taken in a single daily dose].
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Some effects of metolazone on electrolyte transport.
Metolazone action was studied 1) in vitro on isolated operculum of Fundulus heteroclitus (active chloride transport) using an Ussing chamber (metolazone conc 500 microM) and in vivo 2) using the modified Sperber technique in the hen (metolazone infusion rate 0.75-1.2 micrograms/kg/min) and 3) in healthy volunteers using clearance techniques (metolazone infusion rate 10 mg/h). Metolazone reduced (p less than 0.05) short circuit current potential differences with 20% from average control values (p less than 0.05), while direct current resistance was unchanged. This is comparable to thiazide but much lower than loop diuretic effects. True tubular excretion fraction of metolazone before and after novobiocin (2.7 mumol/kg/min coinfusion averaged 14.1 and 4.5%, resp. (p less than 0.01; n = 8). Thus metolazone is partly eliminated by renal tubular secretion. However, the diuretic effect (sodium, chloride and potassium excretion)--and clearances of Cr51-EDTA and I125-Na-o-iodohippurate--were symmetrical, i.e. independent of metolazone urinary excretion rate, as previously shown for thiazides. Renal clearance of metolazone in healthy volunteers. (HPLC-method) averaged 173 +/- 20 ml/min (n = 8). Probenecid (1 g iv.) significantly reduced the renal clearance of metolazone to 33 +/- 7 ml/min and potassium excretion with maximum 30%, while diuretic and saluretic effects were significantly increased with maximum 30%. Thus, also in humans the diuretic effect of metolazone is not coupled to the urinary excretion rate of the drug, but suggests that its diuretic effect is elicited primarily from the peritubular side of the nephron. Probenecid apparently dissociates sodium from potassium excretion effects of metolazone. This implies a luminal, sodium-independent kaliuretic effect of the drug.
Adult↗
Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature.
UNLABELLED: Metolazone is a potent thiazide-like diuretic. It is recommended in severe congestive heart failure (HF). We conducted a review of the existing literature and found that the available information on the use of metolazone in HF is based on studies containing less than 250 patients in total. Nevertheless, metolazone is widely used, often in combination with a loop diuretic. Absorption of metolazone seems to be reduced in HF. Metolazone produces a diuretic response despite a low glomerular filtration rate. A wide dose range of metolazone has been investigated (< or =2.5 to 200 mg), leaving no clear dosing recommendation. However, in most studies a low starting dose (< or =5 mg) was used. We further report an observational study on 21 patients with refractory systolic HF from our specialized outpatient HF clinic. The aim was to evaluate the effects of metolazone in combination with a loop diuretic in contemporary HF patients. RESULTS: We registered 42 episodes of treatment with metolazone. The maximal dose of metolazone was 5 mg. NYHA functional class improved. A significant reduction during treatment in weight, blood pressure, plasma-sodium and -potassium was seen whereas plasma-BUN and -creatinine increased significantly. Clinically important hypokalemia (<2.5 mM) or hyponatremia (<125 mM) were observed during 10% of the treatment episodes. CONCLUSION: The literature review and the observational study support the use of low-dose metolazone (< or =5 mg) on top of oral loop diuretics, as an effective and relatively safe treatment in contemporary outpatients with refractory HF.
Aged↗
Direct effect of metolazone on sodium-dependent transport across the renal brush border membrane.
Studies with clearance and micropuncture techniques indicate that metolazone inhibits transport of sodium and phosphate in the proximal tubule. The present study is focused on transport across the luminal BBM of the proximal tubule to determine whether metolazone has any direct effect on this initial step in transtubular reabsorption. Addition of metolazone (0.01 to 1.00 mM) to isolated renal BBM vesicles caused dose-dependent inhibition (30% to 70%) of the initial uphill phase of Na+ gradient-dependent phosphate transport but did not inhibit the uptake at equilibrium. There were no significant changes in Na+-independent phosphate transport and phosphate transport under nongradient conditions when metolazone was present at 1.0 mM. The initial Na+ gradient-dependent BBM transport of both D-glucose and L-proline was markedly inhibited by 1.0 mM metolazone, indicating the nonspecific inhibitory action of the drug. Metolazone also inhibited efflux of D-glucose and L-proline from vesicles. Neither acetazolamide nor chlorothiazide at 0.1 to 1.0 mM inhibited BBM transport of phosphate, D-glucose, or L-proline. Metolazone did not change significantly BBM transport of Na+, suggesting that inhibition of Na+-dependent transport was not due to major changes in Na+ flux. These in vitro data indicate that metolazone inhibition of phosphate reabsorption in vivo may be due, in part, to a direct effect of metolazone on transport across the BBM of the proximal tubule.
Acetazolamide↗
Addition of metolazone to overcome tolerance to furosemide in infants with bronchopulmonary dysplasia.
A decreased response to the loop diuretic furosemide develops within a few doses in young infants. We tested the hypothesis that the use of the thiazide-like diuretic metolazone, in combination with furosemide, would inhibit water and electrolyte reabsorption and overcome pharmacologic tolerance to furosemide alone. Infants with bronchopulmonary dysplasia of similar gestational and postnatal ages were randomly assigned to one of three groups. Group 1 (n = 6) received furosemide (1 mg/kg per dose) intravenously every 24 hours for a total of five doses. Group 2 (n = 8) received the same treatment as group 1, but in addition metolazone (0.2 mg/kg per dose) was given enterally with doses 3 and 4 of furosemide. Group 3 (n = 8) received metolazone (0.2 mg/kg per dose) enterally every 24 hours for five doses. Urine was collected before the first diuretic dose and throughout the study for determination of the urine flow rate; urinary excretion of sodium, chloride, and potassium; and creatinine clearance. Urinary flow rate and urinary sodium and chloride excretion increased after the first dose in all groups. In the infants treated with either furosemide or metolazone, urinary flow rate and urinary and chloride excretion returned to baseline values after the last three doses. In contrast, when furosemide was administered with metolazone, urinary flow rate and urinary excretion of sodium, chloride, and potassium were greater than the values for baseline and for the previous dose, as well as for the corresponding doses of furosemide in group 1 and metolazone in group 3. Tolerance to furosemide (group 1) and metolazone (group 3) appeared to be explained by compensatory increased sodium and chloride reabsorption without changes in creatinine clearance. We conclude that the administration of metolazone with furosemide enhances diuresis, natriuresis, and chloruresis and overcomes the rapid development of tolerance to furosemide in infants with bronchopulmonary dysplasia by blocking the compensatory increase in renal sodium and chloride absorption.
Bronchopulmonary Dysplasia↗
Metolazone and bendroflumethiazide in hypertension: physiologic and metabolic observations.
A double-blind crossover comparison was made in 18 nonedematous hypertensive subjects with glomerular filtration rates exceeding 70 ml/min/1.73 m2 of the effects of 5 mg metolazone and 5 mg bendroflumethiazide on blood pressure and metabolic parameters. After a 4-wk run-in placebo period, patients received either metolazone or bendroflumethiazide for 6 wk in a crossover fashion with an intervening washout period of 4 wk. Metolazone induced a more sustained and greater blood pressure response than bendroflumethiazide. Changes in plasma potassium, urate, bicarbonate, renin, and angiotensin II occurred during treatment with both metolazone and bendroflumethiazide; the only significant difference, however, was in changes in plasma bicarbonate. Total body potassium (TBK), measured by whole-body monitor, did not fall outside the normal range with either metolazone or bendroflumethiazide, although metolazone induced a greater reduction in TBK (6.2 gm, 5.5% of TBK) than bendroflumethiazide (1.2 gm, 1.1% of TBK, p < 0.05). Our results suggest that metolazone is a more effective antihypertensive and induces similar but greater metabolic changes than bendroflumethiazide. The results of our comparison suggest that although changes in plasma potassium and TBK are minor, they are greater with metolazone, and potassium supplements may not be necessary in nonedematous hypertensive patients with normal renal function.
Adolescent↗
Pharmacokinetic and pharmacodynamic interaction between furosemide and metolazone in man.
In various clinical situations a poor diuretic response to furosemide may be improved by the addition of metolazone. The mechanism of this additive effect is unclear. The purpose of the present investigation was to establish whether metolazone changes the pharmacokinetics of furosemide and by this mechanism enhances the diuretic effect. Eight volunteers were given an intravenous infusion of 4 mg h-1 of furosemide for 12 h. After 6 h 2.5 mg metolazone were administered orally. The addition of metolazone increased diuresis, urinary excretion of sodium and chloride (P less than 0.01), but decreased urinary excretion of calcium (P less than 0.01), while furosemide excretion remained unchanged. Total body clearance and renal clearance values of furosemide were similar before and after administration of metolazone. Our data confirm the additive diuretic effect of the combination treatment metolazone-furosemide and show for the first time a distinct hypocalciuric action of metolazone, similar to thiazides. Moreover metolazone does not affect the pharmacokinetics of furosemide.
Calcium↗
Metolazone and spironolactone in cirrhosis and the nephrotic syndrome.
Eighteen patients with hepatic cirrhosis or nephrotic syndrome and having edema and/or ascites were treated during successive periods with metolazone 5 to 40 mg/day, spironolactone 100 mg/day, and with both diuretics concurrently. Metolazone alone produced a marked diuresis, natriuresis, and weight loss in 8 patients. Spironolactone alone had little effect, but the addition of metolazone renewed diuresis and natriuresis and resulted in additional substantial weight losses in all patients responsive to metolazone alone. Concurrent spironolactone and metolazone also induced moderate diuretic effects in some patients who failed to respond to either drug alone. The drugs were well tolerated; the administration of spironolactone with metolazone prevented decreases in serum potassium, which had occurred during treatment with metolazone alone.
Adult↗
Clinical studies of a new, low-dose formulation of metolazone for the treatment of hypertension.
Two multicenter, double-blind, randomized studies were performed to determine the antihypertensive efficacy and effects on laboratory values of a new, shorter-acting formulation of metolazone in patients with mild to moderate hypertension. After baseline placebo-control periods, 105 patients were randomly assigned to receive single daily doses of either placebo or 0.5, 1.0, or 2.0 mg of the new formulation of metolazone for six weeks in one study, and 164 patients were randomized to receive 0.5, 1.0, or 2.0 mg of the new formulation of metolazone or 2.5 mg of the older, long-acting metolazone in the other. Mean blood pressure reductions in all three metolazone groups were statistically and clinically significant. Blood pressures of 51% to 58% of patients in the 0.5-mg metolazone group were controlled (diastolic blood pressure less than 90 or a fall of greater than or equal to 10 mmHg from baseline). Reductions in mean serum potassium levels were dose-related. We conclude that 0.5 mg of metolazone is safe and effective therapy for hypertension; it will significantly reduce systolic and diastolic blood pressure and minimizes changes in laboratory test values.
Adult↗
Long-term diuretic therapy with metolazone of renal failure and the nephrotic syndrome.
The effects of the new diuretic metolazone were studied in ten patients with chronic renal insufficiency and ten with nephrotic syndrome. Patients were maintained on metolazone for up to 44 months. Beneficial effects of treatment included loss of edema and improved control of blood pressure. The natriuretic effect of metolazone facilitated the use of sodium bicarbonate to treat acidosis in several patients. Concurrent administration of metolazone and furosemide produced a dramatic diuresis in one patient resistant to either diuretic alone. Adverse effects of metolazone therapy were those characteristic of other effective diuretics, Including serum electrolyte losses and hyperuricemia. Initial treatment produced small increases in serum creatinine among patients with renal insufficiency, suggesting that GFR was decreased secondary to diuresis-induced volume depletion. The study demonstrates that metolazone is both safe and effective over long periods of time.
Adult↗
Metolazone pharmacokinetics and pharmacodynamics in renal transplantation.
Metolazone pharmacokinetics and pharmacodynamics were investigated in five renal transplant patients and five creatinine clearance matched controls. Whereas the time to peak metolazone excretion was similar in both groups (with the exception of one renal transplant patient who subsequently was found to have chronic rejection), the percent of the administered dose excreted over 48 h was significantly less in renal transplant patients (8% in renal transplant patients vs 24% in controls). Diminished bioavailability of metolazone or tubular secretion likely accounted for this disparity in metolazone excretion. Both groups developed diuretic tolerance as indicated by hysteresis in the dose response relationship. Cumulative sodium excretion over three successive 12-h time intervals did not differ between groups. Despite this comparable natriuresis, potassium excretion was significantly less in the renal transplant patients during the first day of the study. Accordingly, metolazone administration may provide a means to "unmask" subclinical, tubular secretory dysfunction in the transplanted kidney, as exemplified by defects in metolazone secretion and potassium excretion.
Adult↗
[Furosemide and metolazone: a highly effective diuretic combination].
The natriuretic and diuretic effects of combined treatment with furosemide and metolazone have been studied quantitatively. 15 hospitalized patients with severe fluid retention who showed no reduction of body weight despite treatment with furosemide received metolazone in addition for 3 days. 11 patients had biventricular heart failure with edema, and 4 had cirrhosis of the liver with ascites. Following the addition of metolazone at a starting dose of 2.5 mg/d, a highly significant increase in diuresis and natriuresis, with a corresponding reduction in body weight, was seen in all patients pretreated with a daily dose of 40-370 mg furosemide (mean 122 mg/d). On the first day of this combined treatment the mean sodium excretion increased from 131 to 303 mval/d (2 p less than 0.01) and the mean urine volume increased from 1677 to 2940 ml/d (2 p less than 0.01). The mean reduction in body weight was 6.1 kg (2 p less than 0.001) within 7 days of continuous treatment. Even at low doses metolazone significantly potentiates the diuretic effects of furosemide and therefore simplifies the treatment of fluid retention. High doses of furosemide can be avoided in many cases, a factor of particular advantage in ambulatory long term therapy and in patients with decreased kidney function. It may also lower the cost of the therapy. In 3 patients the furosemide dose had to be lowered after metolazone was started, to avoid an excessive negative fluid balance. These cases clearly demonstrate the importance of daily checks on the patient's body weight after starting combined therapy with furosemide and metolazone.
Ascites↗
Inhibition of binding of [3H]metolazone to rat kidney membrane by stilbene disulfonates.
Thiazide diuretics inhibit an electroneutral chloride and sodium reabsorptive transport pathway in the renal distal convoluted tubule. [3H]Metolazone binds with high affinity to the drug recognition site on the thiazide-sensitive ion transporter. The molecular nature of this transporter is currently unknown. This report examines whether stilbene disulfonates [4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS)], agents that have been used to identify other anion-transporting proteins, could be useful in the identification of the thiazide receptor. We found that high concentrations of DIDS or SITS were required to inhibit binding of [3H]metolazone to rat kidney membranes, with apparent IC50 values of 380 and 940 microM, respectively. The inhibition was due to a decrease in the number of binding sites without alteration in the affinity of the binding. The inhibition was not reversible, as judged by the inability of the inhibition to be reversed by removal of the DIDS or SITS from the membranes prior to equilibration with [3H]metolazone. Addition of 100 mM NaCl to the incubation medium did not protect the [3H]metolazone binding site from inhibition by DIDS. We infer that DIDS and SITS irreversibly inhibit binding of [3H]metolazone by reaction with the thiazide receptor at a site other than the anion-transporting site.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Determination of metolazone in human blood by liquid chromatography with electrospray ionization tandem mass spectrometry.
A rapid, sensitive and accurate liquid chromatographic-tandem mass spectrometric method is described for the determination of metolazone in human blood. Metolazone was extracted from blood using ethyl acetate and separated on a C18 column interfaced with a triple quadrupole tandem mass spectrometer. The mobile phase consisting of a mixture of acetonitrile, 10 mmol/l ammonium acetate and formic acid (60:40:0.1, v/v/v) was delivered at a flow rate of 0.5 ml/min. Electrospray ionization (ESI) source was operated in positive ion mode. Selected reaction monitoring (SRM) mode using the transitions of m/z 366-->m/z 259 and m/z 321-->m/z 275 were used to quantify metolazone and the lorazepam (internal standard), respectively. The linearity was obtained over the concentration range of 0.5-500 ng/ml for metolazone and the lower limit of quantitation (LLOQ) was 0.5 ng/ml. For each level of QC samples, inter- and intra-run precision was less than 8.07 and 3.56% (relative standard deviation (RSD)), respectively, and the bias was within +/-4.0%. This method was successfully applied to the pharmacokinetic study of metolazone formulation after oral administration to humans.
Chromatography, Liquid↗
Thiazide diuretic drug receptors in rat kidney: identification with [3H]metolazone.
Thiazides and related diuretics inhibit NaCl reabsorption in the distal tubule through an unknown mechanism. We report here that [3H]metolazone, a diuretic with a thiazide-like mechanism of action, labels a site in rat kidney membranes that has characteristics of the thiazide-sensitive ion transporter. [3H]Metolazone bound with high affinity (Kd = 4.27 nM) to a site with a density of 0.717 pmol/mg of protein in kidney membranes. The binding site was localized to the renal cortex, with little or no binding in other kidney regions and 11 other tissues. The affinities of thiazide-type diuretics for this binding site were significantly correlated with their clinical potency. Halide anions (Cl-, Br-, and I-) specifically inhibited high-affinity binding of [3H]metolazone to this site. [3H]Metolazone also bound with lower affinity (Kd = 289 nM) to sites present in kidney as well as in liver, testis, lung, brain, heart, and other tissues. Calcium antagonists and certain smooth muscle relaxants had Ki values of 0.6-10 microM for these low-affinity sites, which were not inhibited by most of the thiazide diuretics tested. Properties of the high-affinity [3H]metolazone binding site are consistent with its identity as the receptor for thiazide-type diuretics.
Animals↗
Metolazone and its role in edema management.
Metolazone is commonly administered in conjunction with a loop diuretic to manage volume overload in patients otherwise resistant to loop diuretic therapy alone. Metolazone is a thiazide-type diuretic that is characterized by slow and sometimes erratic absorption when administered as the Zaroxylyn product. This absorptive profile together with the large volume of distribution and high degree of renal clearance for metolazone provide the pharmacologic basis for a favorable diuretic combination effect. Zaroxylyn should always be administered cautiously and only with a means of surveillance allowing the patient's weight to be carefully monitored so as to avoid excessive diuresis. If an excessive diuresis occurs with a metolazone and loop diuretic combination both drugs should be stopped temporarily. The temptation should be avoided to simply reduce the doses of either metolazone or the loop diuretic as a means to controlling an active diuresis.
Diuresis↗
Antihypertensive and renin angiotensin effects of metolazone with and without propranolol.
Renin angiotensin system parameters and blood pressure (B.P.) were followed monthly in patients with essential hypertension on metolazone, 5 mg daily for three months and with added propranolol, 40 to 160 mg, for the subsequent three months. On metolazone alone at three months, sitting B.P. declined from 166/108 +/- 14/11 mm Hg to 145/98 +/- 14/9 mm Hg (P less than 0.005). Plasma renin activity (PRA) increased from 3.9 +/- ng/ml/hr to 10.4 +/- 8.6 ng/ml/hr (P less than 0.005); plasma angiotensinogen did not change. Venous blood angiotensin I and II levels (pg/ml) rose initially but returned toward control values. A significant decline in plasma renin substrate reactivity (PRSr) in index occurred. Propranolol addition caused further lowering of only systolic B.P. and predominantly in the standing position, more marked at one month (40 mg) than at three months (160 mg). No significant further changes were observed in any of the measured parameters of renin angiotensin system, except for a rise in PRSr index concomitant with B.P. elevation at three months. Metolazone-induced changes in B.P. showed significant correlations at three months with changes in PRSr index. It is concluded that during chronic metolazone administration, the overall activity of the renin angiotensin system was diminished or unchanged. Propranolol did not inhibit metolazone stimulated PRA but did cause further decline in B.P. in the first two months, unrelated to renin angiotensin system.
Angiotensin II↗
Thiazide diuretic receptors: autoradiographic localization in rat kidney with [3H]metolazone.
The localization of binding sites for [3H]metolazone, a quinazolinesulfonamide diuretic with thiazide-like actions, was determined by in vitro autoradiography. [3H]Metolazone bound saturably to rat kidney sections incubated in vitro with a dissociation constant (Kd) = 3.4 nM and binding site density = 0.14 pmol/mg of protein. Incubation conditions were used that excluded binding to low affinity sites and carbonic anhydrase. Pharmacological specificity of binding was consistent with labeling of physiologically relevant thiazide diuretic receptors, as identified in previous studies of [3H]metolazone binding to renal membranes. Autoradiographs obtained with tritium-sensitive film demonstrated that binding sites were limited to the renal cortex and were relatively sparsely distributed. Higher resolution autoradiography indicated that [3H] metolazone binding sites were localized in a highly specific manner over short lengths of tubular segments, which by their morphology and distribution most likely represented distal convoluted tubules. In the short sections of tubule that contained receptors, labeling was very dense and appeared to be more prevalent over luminal than peritubular surfaces. The intrarenal distribution of [3H]metolazone binding sites provides further evidence for their identity as thiazide diuretic receptors. These results are consistent with physiological studies demonstrating that the early distal tubule is the location of thiazide-sensitive sodium chloride cotransport.
Animals↗