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Cureus Apr 2020Hyponatraemia is the most common electrolyte imbalance found in hospital population and worldwide thiazide and loop-diuretics are among the most widely used drugs....
Hyponatraemia is the most common electrolyte imbalance found in hospital population and worldwide thiazide and loop-diuretics are among the most widely used drugs. Syndrome of inappropriate antidiuresis diagnosis (SIAD) is complicated in the presence of diuretic therapy due to the misleading clinical assessment of the extracellular volume status, and in order to make SIAD diagnosis it is often necessary to withdraw diuretic therapy. Our study aimed to investigate the diagnostic role of these alternative markers of volume status, serum uric acid (sUA) and fractional excretion of uric acid (FEUA), in hyponatraemic patients treated with different diuretic drugs. Eighty-nine patients were enrolled with the diagnosis of SIAD, diuretic-induced hyponatremia (DIH, treated with furosemide and potassium canrenoate) or thiazide-induced hyponatremia (TIH, treated with hydrochlorothiazide, metolazone or indapamide) and investigated with receiver operating characteristic analysis and a sensitivity test. Our results show that FEUA discriminated better than sUA between SIAD and DIH patients (area under curve 0.96, <0.001 vs. 0.88, <0.001) while it was a poor marker to discriminate between SIAD and TIH (0.65, NS vs. 0.67, NS). In conclusions, FEUA is an excellent marker to discriminate SIAD vs. sodium depleted patients treated with furosemide and/or potassium canrenoate while the diuretic withdrawal, beyond obtaining a serum Na normalization, is still mandatory for differential diagnosis of sodium depleted patients affected by thiazide-induced hyponatraemia.
PubMed: 32455079
DOI: 10.7759/cureus.7762 -
BMJ Case Reports Feb 2020A 62-year-old woman with chronic kidney disease stage 4, sleep apnoea on continuous positive airway pressure and recent admission for acute-on-chronic diastolic heart...
A 62-year-old woman with chronic kidney disease stage 4, sleep apnoea on continuous positive airway pressure and recent admission for acute-on-chronic diastolic heart failure presented to emergency room with weakness. She was hypotensive and had symptomatic bradycardia in the 30 s secondary to hyperkalaemia and beta-blockers, raising concern for BRASH syndrome. Antihypertensives were immediately held. Potassium-lowering agents (with calcium gluconate for cardiac stability) were begun, as were fluids and dopamine for vasopressor support. The patient was admitted to intensive care unit and electrophysiology was consulted. Over the next 2 days, the patient clinically improved: she remained off dopamine for over 24 hours; potassium levels and renal function improved; and heart rate stabilised in 60 s. The patient was eventually discharged and advised to avoid metolazone, bumetanide and carvedilol, with primary care provider and cardiology follow-up.
Topics: Antihypertensive Agents; Atrioventricular Block; Bradycardia; Bumetanide; Carvedilol; Female; Humans; Hyperkalemia; Metolazone; Middle Aged; Renal Insufficiency; Shock; Syndrome; Vasoconstrictor Agents
PubMed: 32094236
DOI: 10.1136/bcr-2019-233825 -
Journal of Chromatographic Science Apr 2020Two robust and selective stability-indicating chromatographic methods were developed and validated for the determination of metolazone in drug substance and...
Development and Validation of Two Robust Stability-Indicating Chromatographic Methods for Determination of Metolazone in Drug Substance and Pharmaceutical Dosage Form in the Presence of Its Degradation Products and Characterization of Main Degradation Products Based on LC-MS.
Two robust and selective stability-indicating chromatographic methods were developed and validated for the determination of metolazone in drug substance and pharmaceutical dosage form in the presence of its degradation products. The HPLC method employed a Kromasil C18 (250 × 4.6,5 μm) column and a mobile phase of acetonitrile: 0.2% orthophosphoric acid (32:68 v/v) at a flow rate 2 mL/min and detection at 238 nm. The separation was performed in HPLC isocratic mode. The robustness of the suggested method was assessed using the Plackett-Burman design, parameters affecting system suitability were established and non-significant intervals for the significant parameters were considered. The HPTLC method employed Nano-SIL-20 UV254 HPTLC plates as adsorbent, ethyl acetate: toluene: acetic acid solution (4:4:0.5, v/v/v), as a developing solvent system and densitometric detection at 238 nm. Metolazone was exposed to different stress conditions, including acid and alkaline hydrolysis and oxidative and photolytic degradation. The main degradation products obtained have been characterized and interpreted based on LC-MS. The linearity of the suggested methods was proved in the concentration range of 20-75 μg/mL for the HPLC method and 100-900 ng/spot for the HPTLC method. The suggested methods were validated according to international conference on harmonization guidelines. These methods were successfully dedicated for the estimation of metolazone in drug substance and pharmaceutical dosage form in the presence of its degradation products. The results of the suggested methods were evaluated and compared statistically with results obtained by an official method without finding any significant difference.
Topics: Calibration; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Chromatography, Thin Layer; Drug Stability; Hydrolysis; Mass Spectrometry; Metolazone; Tablets
PubMed: 31879759
DOI: 10.1093/chromsci/bmz110 -
JPMA. the Journal of the Pakistan... Dec 2019To compare efficacy and safety of indapamide-furosemide combination against metolazone-furosemide combination in refractory heart failure patients. (Randomized Controlled Trial)
Randomized Controlled Trial
Comparing the sodium excreting efficacy of furosemide and indapamide combination against furosemide and metolazone combination in congestive heart failure patients: A randomized control trial.
OBJECTIVE
To compare efficacy and safety of indapamide-furosemide combination against metolazone-furosemide combination in refractory heart failure patients.
METHODS
The randomised controlled trial was conducted at Rehman Medical Institute, Peshawar, Pakistan, from January 1 to June 30, 2018, and comprised refractory heart failure patients who were randomised into two groups using lottery method Group 1 received intravenous furosemide 40mg Q12hr with metolazone 5mg Q24hr, while group 2 received intravenous furosemide 40mg Q12hr with indapamide 2.5mg Q24hr. Both groups were assessed for urinary sodium excretion, total urine output and decrease in weight on day one, day three and day five of admission. SPSS 22 was used for data analysis.
RESULTS
Of the 150 patients, there were 75(50%) in each of the two groups. Mean age in group 1 was 64.8}11.2 years, while it was 66.3}12.9 years in group 2. Both groups showed increased urinary sodium excretion and total urine output (p>0.05). Hypokalaemia was the most common adverse event 66%. Mean hospital stay was not significantly different between the groups (p>0.05).
CONCLUSIONS
There was no significant differences between adverse events and efficacy between patients receiving either indapamide-furosemide combination or metolazone-furosemide combination.
Topics: Administration, Intravenous; Administration, Oral; Aged; Body Weight; Diuretics; Drug Therapy, Combination; Female; Furosemide; Heart Failure; Humans; Indapamide; Male; Metolazone; Middle Aged; Pakistan; Sodium
PubMed: 31853105
DOI: 10.5455/JPMA.3401 -
JACC. Heart Failure Mar 2020This study compared combination diuretic strategies in acute heart failure (AHF) complicated by diuretic resistance (DR). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
This study compared combination diuretic strategies in acute heart failure (AHF) complicated by diuretic resistance (DR).
BACKGROUND
Combination diuretic regimens to overcome loop DR are commonly used but with limited evidence.
METHODS
This study was a randomized, double-blinded trial in 60 patients hospitalized with AHF and intravenous (IV) loop DR. Patients were randomized to oral metolazone, IV chlorothiazide, or tolvaptan therapy. All patients received concomitant high-dose IV infusions of furosemide. The primary outcome was 48-h weight loss.
RESULTS
The cohort exhibited DR prior to enrollment, producing 1,188 ± 476 ml of urine in 12 h during high-dose loop diuretic therapy (IV furosemide: 612 ± 439 mg/day). All 3 interventions significantly improved diuretic efficacy (p < 0.001). Compared to metolazone (4.6 ± 2.7 kg), neither IV chlorothiazide (5.8 ± 2.7 kg; 1.2 kg [95% confidence interval (CI)]: -2.9 to 0.6; p = 0.292) nor tolvaptan (4.1 ± 3.3 kg; 0.5 kg [95% CI: -1.5 to 2.4; p = 0.456) resulted in more weight loss at 48 h. Median (interquartile range [IQR]) cumulative urine output increased significantly and did not differ among those receiving metolazone (7.78 [IQR: 6.59 to 10.10] l) and chlorothiazide (8.77 [IQR: 7.37 to 10.86] l; p = 0.245) or tolvaptan (9.70 [IQR: 6.36 to 13.81] l; p = 0.160). Serum sodium decreased less with tolvaptan than with metolazone (+4 ± 5 vs. -1 ± 3 mEq/l; p = 0.001), but 48-h spot urine sodium was lower with tolvaptan (58 ± 25 mmol/l) than with metolazone (104 ± 16 mmol/l; p = 0.002) and with chlorothiazide (117 ± 14 mmol/l; p < 0.001).
CONCLUSIONS
In this moderately sized DR trial, weight loss was excellent with the addition of metolazone, IV chlorothiazide, or tolvaptan to loop diuretics, without a detectable between-group difference. (Comparison of Oral or Intravenous Thiazides vs. tolvaptan in Diuretic Resistant Decompensated Heart Failure [3T]; NCT02606253).
Topics: Administration, Oral; Aged; Chlorothiazide; Diuretics; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Furosemide; Heart Failure; Humans; Infusions, Intravenous; Male; Metolazone; Middle Aged; Prospective Studies; Retrospective Studies; Tolvaptan; Treatment Outcome
PubMed: 31838029
DOI: 10.1016/j.jchf.2019.09.012 -
Hospital Pharmacy Dec 2019Thiazide diuretics are often utilized to overcome loop diuretic resistance when treating acute decompensated heart failure (ADHF). In addition to a large cost...
Thiazide diuretics are often utilized to overcome loop diuretic resistance when treating acute decompensated heart failure (ADHF). In addition to a large cost advantage, several pharmacokinetic advantages exist when administering oral metolazone (MTZ) compared with intravenous (IV) chlorothiazide (CTZ), yet many providers are reluctant to utilize an oral formulation to treat ADHF. The purpose of this study was to compare the increase in 24-hour total urine output (UOP) after adding MTZ or CTZ to IV loop diuretics (LD) in patients with heart failure with reduced ejection fraction (HFrEF). From September 2013 to August 2016, 1002 patients admitted for ADHF received either MTZ or CTZ in addition to LD. Patients were excluded for heart failure with preserved ejection fraction (HFpEF) (n = 469), <24-hour LD or UOP data prior to drug initiation (n = 129), or low dose MTZ/CTZ (n = 91). A total of 168 patients were included with 64% receiving CTZ. No significant difference was observed between the increase in 24-hour total UOP after MTZ or CTZ initiation (1458 [514, 2401] mL vs 1820 [890, 2750] mL, = .251). Both MTZ and CTZ similarly increased UOP when utilized as an adjunct to IV LD. These results suggest that while thiazide agents can substantially increase UOP in ADHF patients with HFrEF, MTZ and CTZ have comparable effects.
PubMed: 31762481
DOI: 10.1177/0018578718795855 -
American Journal of Kidney Diseases :... Feb 2020Hyponatremia can complicate thiazide use in a minority of susceptible individuals and can result in significant morbidity and even mortality. Risk factors for... (Review)
Review
Hyponatremia can complicate thiazide use in a minority of susceptible individuals and can result in significant morbidity and even mortality. Risk factors for thiazide-associated hyponatremia include age, female sex, and possibly low body mass. A genetic susceptibility has recently been uncovered. Although frequently developing early after thiazide treatment initiation, many cases of hyponatremia present after months or years of use. Many cases are asymptomatic or have mild symptoms, but seizures and/or coma may develop, especially in those with acute onset. The pathophysiology is incompletely understood and includes some combination of excessive fluid intake, cation (sodium and potassium) depletion, osmotic inactivation of sodium, and reduced ability to excrete free water. Reduced distal delivery of filtrate, reduced solute load (urea), direct inhibition of the sodium-chloride cotransporter, and increased collecting duct permeability to water mediated by some combination of antidiuretic hormone, prostaglandins, and thiazides themselves may contribute to this diluting defect. The predominant pathophysiologic mechanism(s) varies from patient to patient. The cornerstone of therapy is cessation of thiazide use, cation repletion, and oral fluid restriction. If severely symptomatic, 3% saline solution may be indicated. Overly rapid correction of chronic hyponatremia must be avoided in all cases.
Topics: Biomarkers; Humans; Hypertension; Hyponatremia; Sodium; Thiazides
PubMed: 31606239
DOI: 10.1053/j.ajkd.2019.07.011 -
Molecules (Basel, Switzerland) Jul 2019This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical...
This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical ingredients (APIs). Spray-dried, fully amorphous indapamide, metolazone, glibenclamide, hydrocortisone, hydrochlorothiazide, ketoconazole, and sulfathiazole were used as model APIs. The parameters used to assess the supersaturation potential and crystallization kinetics were the maximum supersaturation concentration (C), the area under the curve (AUC), and the crystallization rate constant (k). These were compared for freshly spray-dried and aged/crystallized samples. Aged samples were stored at 75% relative humidity for 168 days (6 months) or until they were completely crystallized, whichever came first. The solid-state changes were monitored with differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. Supersaturation potential and crystallization kinetics were investigated using a tenfold supersaturation ratio compared to the thermodynamic solubility using the µDISS Profiler. The physically aged indapamide and metolazone and the minimally crystallized glibenclamide and hydrocortisone did not show significant differences in their C and AUC when compared to the freshly spray-dried samples. Ketoconazole, with a crystalline content of 23%, reduced its C and AUC by 50%, with C being the same as the crystalline solubility. The AUC of aged metolazone, one of the two compounds that remained completely amorphous after storage, significantly improved as the crystallization kinetics significantly decreased. Glibenclamide improved the most in its supersaturation potential from amorphization. The study also revealed that, besides solid-state crystallization during storage, crystallization during dissolution and its corresponding pathway may significantly compromise the supersaturation potential of fully amorphous APIs.
Topics: Calorimetry, Differential Scanning; Chemical Phenomena; Crystallization; Drug Stability; Kinetics; Pharmaceutical Preparations; Preservation, Biological; Solubility; Spectrum Analysis, Raman; Time Factors
PubMed: 31357587
DOI: 10.3390/molecules24152731 -
Luminescence : the Journal of... Sep 2019Synchronous spectrofluorimetry is utilized to carry out a rapid, sensitive and reliable method for determination of the binary mixture of metolazone (MTL) and losartan...
Synchronous spectrofluorimetry is utilized to carry out a rapid, sensitive and reliable method for determination of the binary mixture of metolazone (MTL) and losartan potassium (LSP). Under optimized experimental conditions, the synchronized fluorescence spectra of the two drugs were measured at Δλ = 80 nm in acidic methanolic solution and intensities were recorded at 260 nm for MTL and 335 nm for LSP. Linear correlation between fluorescence intensity and concentration were obtained through the ranges 0.02-0.2 μg/mL and 0.2-2.0 μg/mL for MTL and LSP, respectively. Limits of detection were 3.02 and 0.12 ng/mL, whereas limits of quantification were 9.16 and 0.35 ng/mL for MTL and LSP, respectively. The designated procedure was easily and successfully adopted to determine the two compounds in their single, as well as in co-formulated, tablets and the results showed high precision and accuracy without any significant interference from common tablet excipients. A comparison of the obtained results with a published reference method was carried out and both showed good agreement with respect to accuracy and precision.
Topics: Antihypertensive Agents; Fluorescence; Losartan; Metolazone; Spectrometry, Fluorescence; Tablets
PubMed: 31111664
DOI: 10.1002/bio.3646