Search

Thiazide, thiazide-like, and loop diuretics are primarily known for inhibiting members of the SLC12A family of Cl- transporters, which include the Na+Cl- cotransporter (NCC), Na+K+2Cl- cotransporters (NKCC1 and NKCC2) and K+Cl- symporters (KCC1-4). While the main pharmacological effect of these diuretics is diuresis, achieved by promoting the excretion of excess water and salt through the kidneys, they have intriguing pharmacological effects beyond their traditional ones which cannot be solely attributed to their effects on renal salt transport. Of particular interest is their role in modulating inflammatory processes. These diuretics appear to exert both pro- and anti-inflammatory effects, potentially by influencing various pathways involved in immune responses. For example, NKCC1 has been implicated in the regulation of pro-inflammatory cytokines, such as interleukin-1β (IL1β), interleukin-8 (IL8) and tumor necrosis factor α (TNFα), which are critical mediators of immune cell activity during inflammation. The underlying mechanisms through which NKCC1 contributes to inflammation may involve key signaling pathways, such as that mediated by the nuclear factor kappa B (NFκB). This pathway is crucial for the activation and assembly of the inflammasome, as well as for regulating the phagocytic activity of immune cells. In addition, NKCC1 can control (or be controlled) by reactive oxygen species and oxidative stress, which contribute to the pathogenesis of various inflammatory conditions as well. Diuretics may help mitigate inflammation-related tissue damage by scavenging reactive oxygen species and boosting antioxidant defenses, thereby restoring redox balance in inflamed tissues. Despite these intriguing effects, the precise molecular pathways through which thiazide, thiazide-like and loop diuretics may modulate inflammatory responses remain poorly understood and warrant further investigation. This aspect of their pharmacological profile highlights their potential for therapeutic use beyond the scope of traditional diuretic functions. [ABSTRACT FROM AUTHOR]

Introduction: The literature lacks whether metabolic alkalemia occurs in outpatients with hypercalciuric nephrolithiasis. Thus, we aim to investigate it because these patients are often treated with thiazides to reduce urinary calcium excretion. However, thiazides induce chloride losses due to the inhibition of Na-Cl cotransporter expressed in the renal distal tubule cells. Besides thiazide prescription, many of these patients are also supplemented with potassium citrate, which is an addition of alkali source in their bodies. Methods: We collected clinical, demographic characteristics, and laboratory data from electronic medical charts of outpatients with calcium kidney stones followed in our institution from January 2013 to July 2021. We diagnosed those cases as metabolic alkalemia, in which the venous blood gas tests showed pH ≥7.46 and bicarbonate concentration >26 mEq/L. Then, we applied statistical analysis to compare distinct categories between patients with and without metabolic alkalemia. Results: We diagnosed metabolic alkalemia in 4.3% of hypercalciuric nephrolithiasis outpatients, and we verified that thiazides had been used in all of them except in one case. Furthermore, we observed that the amount of thiazide taken daily was higher in patients with metabolic alkalemia than in those without this imbalance. Additionally, hypokalemia was present in 37% of patients who developed metabolic alkalemia. We also found lower chloride, magnesium and ionic calcium serum concentrations in patients with metabolic alkalemia than in those without an acid-base disequilibrium. Conclusion: Despite the low prevalence of metabolic alkalemia in hypercalciuric kidney stone formers, it is important to monitor these patients due to the high incidence of hypokalemia and the potential presence of other electrolyte disorders. [ABSTRACT FROM AUTHOR]

• In patients with acute heart failure, it is recommended to add a second diuretic early if the patient has not responded adequately to the initial diuretic. • The combination of thiazide and loop diuretics at discharge was not associated with a risk of adverse clinical events. • The effect of a nephron blockade strategy using in the outpatient setting after a recent episode of AHF is sure. To investigate the association of the addition of thiazide diuretic on top of loop diuretic and standard of care with short-term outcomes of patients discharged after surviving an acute heart failure (AHF) episode. This is a secondary analysis of 14,403 patients from three independent cohorts representing the main departments involved in AHF treatment for whom treatment at discharge was recorded and included loop diuretics. Patients were divided according to whether treatment included or not thiazide diuretics. Short-term outcomes consisted of 30-day all-cause mortality, hospitalization (with a separate analysis for hospitalization due to AHF or to other causes) and the combination of death and hospitalization. The association between thiazide diuretics on short-term outcomes was explored by Cox regression and expressed as hazard ratios (HR) with 95 % confidence intervals, which were adjusted for 18 patient-related variables and 9 additional drugs (aside from loop and thiazide diuretics) prescribed at discharge. The median age was 81 (interquartile range=73–86) years, 53 % were women, and patients were mainly discharged from the cardiology (42 %), internal medicine or geriatric department (29 %) and emergency department (19 %). There were 1,367 patients (9.5 %) discharged with thiazide and loop diuretics, while the rest (13,036; 90.5 %) were discharged with only loop diuretics on top of the remaining standard of care treatments. The combination of thiazide and loop diuretics showed a neutral effect on all outcomes: death (adjusted HR 1.149, 0.850–1.552), hospitalization (0.898, 0.770–1.048; hospitalization due to AHF 0.799, 0.599–1.065; hospitalization due to other causes 1.136, 0.756–1.708) and combined event (0.934, 0.811–1.076). The combination of thiazide and loop diuretics was not associated with changes in risk of death, hospitalization or a combination of both. [ABSTRACT FROM AUTHOR]

Acute heart failure (AHF) is a serious condition with a high mortality rate. It is considered as the most common cause of unplanned hospitalizations in the elderly population. In 90% of all cases AHF presents with congestive symptoms, thus mostly treated with loop diuretics. However, in some cases resistance to loop diuretics develops, causing a major problem. In these cases, despite diuretic treatment, urinary output remains inadequate. Resistance, apart from leading to longer hospitalization and inadequate improvement of congestion, has been shown to be responsible for a worse prognosis compared to properly established diuretic response. Thus, managing resistance is important for which the addition of other diuretics (acting at other targets) may be a solution. The most widely studied of these are thiazide diuretics. Although, previous research suggests that thiazides may be effective in treating diuretic resistance, their early side effects can significantly affect patient survival, therefore their use in combination has not yet been widely adopted. However, the recent CLOROTIC trial has provided promising results on this issue. In our review, we are investigating the use of thiazides in the acute heart failure population in the presence of loop diuretic resistance in the light of these new results.

Purpose of Review: Diuretics are the cornerstone therapy for acute heart failure (HF) and congestion. Patients chronically exposed to loop diuretics may develop diuretic resistance as a consequence of nephron remodelling, and the combination of diuretics will be necessary to improve diuretic response and achieve decongestion. This review integrates data from recent research and offers a practical approach to current pharmacologic therapies to manage congestion in HF with a focus on combinational therapy. Recent Findings: Until recently, combined diuretic treatment was based on observational studies and expert opinion. Recent evidence from clinical trials has shown that combined diuretic treatment can be started earlier without escalating the doses of loop diuretics with an adequate safety profile. Summary: Diuretic combination is a promising strategy for overcoming diuretic resistance in HF. Further studies aiming to get more insights into the pathophysiology of diuretic resistance and large clinical trials confirming the safety and efficacy over standard diuretics regimens are warranted. [ABSTRACT FROM AUTHOR]

Objective: Thiazides are the first‐line treatment for hypertension, however, they have been associated with hospitalizations for thiazide‐associated hyponatremia (TAH). The aim of this study was to evaluate the risk of TAH and other drug‐associated hyponatremia in a Korean population. Methods: The study used big data from the National Health Insurance Sharing Service of 1,943,345 adults treated for hypertension from January 2014 to December 2016. The participants were divided into two groups based on the use of thiazides. Cox proportional hazard models were used to identify independent risk factors for the occurrence of hyponatremia. Results: The study found that hyponatremia‐related hospitalizations were significantly higher in the thiazide group than the control group (2.19% vs. 1.45%). The risk increased further with concurrent use of other diuretics or desmopressin, and thiazide+spironolactone+desmopressin and hospitalization risk further increased (4.0 and 6.9 times). Multivariate analysis showed that hyponatremia occurrence increased with age, diabetes mellitus, depression, and thiazide use (hazard ratio = 1.436, p < 0.001). The thiazide group had better 6‐year overall survival than the control group but had more fractures and hyponatremia. Conclusions: Thiazide use is associated with an increased risk of hyponatremia and related complications. However, the mortality rate decreased in those who received thiazides, suggesting that thiazide use itself is not harmful and may help decrease complications and improve prognosis with proper, cautious use in high‐risk patients. [ABSTRACT FROM AUTHOR]

IntroductionEffective, equity-promoting interventions implemented by health care systems are needed to address health care disparities and population-level health disparities. We evaluated the impact of a clinical decision support tool to improve evidence-based thiazide diuretic prescribing among Black patients to address racial disparities in hypertension control.MethodsWe employed an interrupted time series design and qualitative interviews to evaluate the implementation of the tool. Our primary outcome measure was the monthly rate of thiazide use among eligible patients before and after implementation of the tool (January 2013-December 2016). We modeled month-to-month changes in thiazide use for Black and White patients, overall, and by sex and medical center racial composition. We conducted key informant interviews to identify modifiable facilitators and barriers to implementation of the tool across medical centers.ResultsOf the 318,720 patients, 15.5% were Black. We observed no change in thiazide use or blood pressure control following the implementation of the tool in either racial subgroup. There was a slight but statistically significant reduction (2.32 percentage points, p < 0.01) in thiazide use among Black patients following the removal the tool that was not observed among White patients. Factors affecting the tool's implementation included physician and pharmacist resistance to thiazide use and a lack of ongoing promotion of the tool.DiscussionThe clinical decision support tool was insufficient to change prescribing practices and improve blood pressure control among Black patients.ConclusionsFuture interventions should consider physician attitudes about thiazide prescribing and the importance of multilevel approaches to address hypertension disparities.

This article explores the sex differences in the treatment of arterial hypertension, focusing on the influence of sex hormones on the effectiveness and side effects of antihypertensive drugs. It notes that thiazide diuretics are more effective in women but may cause more adverse effects. The article also discusses the higher rates of treatment and control of arterial hypertension in women compared to men, particularly in Latin America and the Caribbean. However, older women have lower control rates, and the reasons for these differences are not fully understood. The text emphasizes the need for further research and evidence to optimize treatment for women, particularly menopausal women. [Extracted from the article]

Copyright of Osmangazi Journal of Medicine / Osmangazi Tip Dergisi is the property of Eskisehir Osmangazi University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Thiazide diuretics are first-line drugs for the treatment of hypertension, but hypertension treatment guidelines have systematically discouraged their use in patients with advanced chronic kidney disease (CKD). For the first time, a systematic review and random-effects meta-analysis were performed to assess the effectiveness of thiazides and thiazide-like diuretics to treat hypertension in patients with stages 3b, 4, and 5 CKD. A systematic review and random-effects meta-analysis that included a literature search using the following databases were performed: MEDLINE through PubMed, Cochrane Database of Systematic Reviews (CDSR) and Cochrane Central Register of Controlled Trials (CENTRAL) through the Cochrane Library, Embase, and ISI – Web of Science (all databases). Prospective studies that evaluated the effectiveness of thiazide and thiazide-like diuretics in individuals with a GFR < 45 mL/min/1.73 m2 were included. Five clinical trials, totaling 214 participants, were included, and the mean GFR ranged from 13.0 ± 5.9 mL/min/1.73 m2 to 26.8 ± 8.8 mL/min/1.73 m2. There was evidence of a reduction in mean blood pressure and in GFR, as well as in fractional sodium excretion and fractional chloride excretion. Thiazide and thiazide-like diuretics seem to maintain their effectiveness in lowering blood pressure in patients with advanced chronic kidney disease. These findings should spur new prospective randomized trials and spark discussions, particularly about upcoming hypertension guidelines. [ABSTRACT FROM AUTHOR]

Aims: In patients with acute heart failure (AHF), the addition of hydrochlorothiazide (HCTZ) to furosemide improved diuretic response in the CLOROTIC trial. This work aimed to evaluate if these effects differ across the estimated glomerular filtration rate (eGFR) spectrum. Methods and results: This post‐hoc analysis of the CLOROTIC trial analysed 230 patients with AHF and explored the influence of eGFR on primary and secondary endpoints. The median eGFR was 43 ml/min/1.73 m2 (range 14–109) and 23% had eGFR ≥60 ml/min/1.73 m2 (group 1), 24% from 45 to 59 ml/min/1.73 m2 (group 2), and 53% <45 ml/min/1.73 m2 (group 3). Patients treated with HCTZ had greatest weight loss at 72 h in all three groups, but patients in group 1 had a significantly greater response (−2.1 kg [−3.0 to 0.5]), compared to patients in groups 2 (−1.3 kg [−2.3 to 0.2]) and 3 (−0.1 kg [−1.3 to 0.4]) (p‐value for interaction = 0.246). At 96 h, the differences in weight were −1.8 kg (−3.0 to −0.3), −1.4 kg (−2.6 to 0.3), and −0.5 kg (−1.3 to −0.1) in groups 1, 2, and 3, respectively (p‐value for interaction = 0.256). There were no significant differences observed with the addition of HCTZ in terms of diuretic response, mortality or rehospitalizations, or safety endpoints (impaired renal function, hyponatraemia, and hypokalaemia) among the three eGFR groups (all p‐values for interaction were no significant). Conclusion: The addition of eGFR‐adjusted doses of oral HCTZ to loop diuretics in patients with AHF improved diuretic response across the eGFR spectrum. Clinical Trial Registration: ClinicalTrials.gov: NCT01647932; EudraCT number: 2013–001852‐36. [ABSTRACT FROM AUTHOR]

Context: Differential diagnosis of thiazide-associated hyponatremia (TAH) is challenging. Patients can either have volume depletion or a syndrome of inappropriate antidiuresis (SIAD)-like presentation. Objective: To evaluate the impact of the simplified apparent strong ion difference in serum (aSID; sodium + potassium -- chloride) as well as the urine chloride and potassium score (ChU; chloride -- potassium in urine) in the differential diagnosis of TAH, in addition to assessment of fractional uric acid excretion (FUA). Methods: Post hoc analysis of prospectively collected data from June 2011 to August 2013 from 98 hospitalized patients with TAH < 125 mmol/L enrolled at University Hospital Basel and University Medical Clinic Aarau, Switzerland. Patients were categorized according to treatment response in volume-depleted TAH requiring volume substitution or SIAD-like TAH requiring fluid restriction. We computed sensitivity analyses with ROC curves for positive predictive value (PPV) and negative predictive value (NPV) of aSID, ChU, and FUA in differential diagnosis of TAH. Results: An aSID > 42 mmol/L had a PPV of 79.1% in identifying patients with volume-depleted TAH, whereas a value < 39 mmol/L excluded it with a NPV of 76.5%. In patients for whom aSID was inconclusive, a ChU < 15 mmol/L had a PPV of 100% and a NPV of 83.3%, whereas FUA < 12% had a PPV of 85.7% and a NPV of 64.3% in identifying patients with volume-depleted TAH. Conclusion: In patients with TAH, assessment of aSID, potassium, and chloride in urine can help identifying patients with volume-depleted TAH requiring fluid substitution vs patients with SIAD-like TAH requiring fluid restriction. [ABSTRACT FROM AUTHOR]

Thiazides are in common use also in people over 65 years of age. Their side effects before the age of 60 are not very common and usually refer to the development of hypokalemia. In the elderly, the number of complications after thiazides increases significantly, and the most common side effect is hyponatremia. Although mild hyponatremia is usually asymptomatic, more severe cases may cause weakness, appetite loss, nausea, vomiting, and dizziness. However, even asymptomatic hyponatremia increases mortality. The therapy depends on the clinical picture and requires a reduction in fluid intake (in patients with symptoms of inadequate vasopressin secretion) or hydration and administration of salt solution (in patients with symptoms of decreased extracellular space). The treatment with thiazides may increase the risk of skin cancer due to fotosensibilsation. [ABSTRACT FROM AUTHOR]

Abstract Background Previous findings on the associations of thiazide use with skin cancers were conflicting. This study aimed to examine the associations of individual thiazide use with skin cancer risk, differentiated by subtypes of skin cancers, geographic regions, and cumulative doses of individual thiazides. Methods We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for relevant studies on January 5, 2022, scanned the references of included studies, and consulted experts. We included case-control and cohort studies or randomized trials reporting the associations of individual thiazide or thiazide-like diuretics use with skin cancers. Non-melanoma skin cancer (NMSC) and melanoma were analysed separately. A random-effects model meta-analysis was conducted for pooled odds ratio (OR) and hazard ratio (HR) for skin cancers related to individual thiazide use. Results We included 15, 5, and 5 case-control or cohort studies reporting the risk for skin cancers associated with hydrochlorothiazide, bendroflumethiazide, and indapamide use, respectively, with 17,848,313 participants. The meta-analysis showed associations of hydrochlorothiazide use with increased risk of NMSC (OR 1.16, 95% CI 1.08–1.24; HR 1.26, 95% CI 1.04–1.54), squamous cell carcinoma (SCC) (OR 1.32, 95% CI 1.06–1.65; HR 1.61, 95% CI 0.97–2.67), and melanoma (OR 1.11, 95% CI 1.02–1.20; HR 1.03, 95% CI 0.93–1.14). The increased risks for SCC were associated with high cumulative doses of hydrochlorothiazide (OR 2.56, 95% CI 1.43–4.57; HR 1.20, 95% CI 1.00–1.45). Hydrochlorothiazide use was associated with different subtypes of melanoma including superficial spreading (OR 1.18, 95% CI 1.05–1.33), nodular (OR 1.23, 95% CI 1.08–1.39), and lentigo maligna melanoma (OR 1.33, 95% CI 1.08–1.65). Various cumulative doses of hydrochlorothiazide were associated with increased odds for melanoma. However, the associations of hydrochlorothiazide use with increased risk of NMSC and melanoma only appeared in non-Asian countries. No meaningful increase in the risk for skin cancers was associated with bendroflumethiazide and indapamide. Conclusions Hydrochlorothiazide is associated with an increased risk for NMSC (especially SCC) and melanoma in non-Asian countries, whereas bendroflumethiazide and indapamide are not associated with a meaningful risk for skin cancers. Healthcare professionals and patients should be informed of the different risk profiles of skin cancers associated with different thiazides, cumulative doses, and regions. Trial registration PROSPERO CRD42021234317 .

Resumen: La hidroclorotiazida (HCTZ) y otros diuréticos tiazídicos son fármacos que se han empleado desde hace décadas para el tratamiento de la hipertensión arterial, la insuficiencia cardíaca o la enfermedad renal crónica. Las tiazidas se han asociado con reacciones de fotosensibilidad, siendo heterogéneas en cuanto a manifestación clínica y tiempo de recuperación, y en las cuales, el fototest, el fotoparche y la biopsia cutánea nos pueden ser útiles en el diagnóstico. En relación con estos fármacos, en los últimos años se ha evidenciado también un mayor riesgo dosis-dependiente de desarrollar determinados tipos de cáncer cutáneo en pacientes tratados de forma crónica con HCTZ. En esta revisión se comentan, asimismo, otros efectos adversos menos habituales o reconocidos de los diuréticos tiazídicos reportados de forma aislada en la literatura. Abstract: Hydrochlorothiazide and other thiazide diuretics have been used for decades to treat high blood pressure, heart failure, and chronic kidney disease. Thiazides have been linked to photosensitivity with heterogeneous clinical manifestations and recovery times. Diagnosis can be aided by phototesting, photopatch testing, and skin biopsy. Long-term use of hydrochlorothiazide has been linked to an increased dose-dependent risk of certain types of skin cancer in recent years. In this review, we also look at other less common or lesser-known adverse effects of thiazide diuretics that have been described in isolated reports.

Yuanyuan Fan,1,&ast; Nazeer Hussain Khan,1,&ast; Muhammad Farhan Ali Khan,2 MD Faysal Ahammad,3 Tayyaba Zulfiqar,2 Razia Virk,4 Enshe Jiang5 1School of Life Sciences, Henan University, Kaifeng, Henan, 475004, People’s Republic of China; 2Department of Pharmacy, Quaid I Azam University, Islamabad, Pakistan; 3Key Laboratory of Natural Medicine and Immune Engineering, School of Medicine, Henan University, Kaifeng, People’s Republic of China; 4Department of Bio-Sciences, University Wah, Rawalpindi, Pakistan; 5Institute of Nursing and Health, Henan University, Kaifeng, 475004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Enshe Jiang, Email esjiang@gmail.comAbstract: Breast cancer (BC) is the most common malignancy affecting women, and its incidence in younger women is rising worldwide. Early-onset of BC is a multi-step process involving various biological aggressive tumors such as triple negative and human epidermal growth factor 2 (HER2)-positive cancers. BC prevention is still arduous across the globe. A series of observational studies have established a conclusive non-genetic clinical link between hypertension (HTN) and the development of invasive BC. Those clinical associations have driven a pharmacological seek to use the anti-hypertension (AHTN) drugs as an effective adjunctive in BC therapy. The use of AHTN, especially beta-blockers and thiazides, has been recognized as a potent anti-tumor drug to mitigate BC progression, reduce the side effects of cancer treatment, and stop the reoccurrence of cancer in the survivors. Considering the dire need to disseminate the research on how AHTN drugs can be opted as the effective adjunctive therapy to cure the BC, the current review aimed to provide an update on novel understandings on association and mechanisms of AHTN-drugs against BC as an additional cancer therapy.Keywords: breast cancer, beta blockers, hypertension, hypertensive drugs, thiazides

The latest treatment guidelines for patients with arterial hypertension continues to indicate as the first line therapy a minimal association between renin-angiotensin system (RAS) blockers and a thiazide-type or a thiazide-like diuretic. In addition, according to 2018 ESC/ESH (European Society of Cardiology/European Society of Hypertension) guidelines for the management of arterial hypertension, a mineralocorticoid receptor antagonist may be added in resistant hypertension cases (uncontrolled hypertension under at least 3 classes of antihypertensive drugs including a RAS blocker, thiazide diuretic and a calcium channel blocker) for general population. For chronic kidney disease (CKD) patients, achieving the optimal blood pressure (BP) level can be difficult because high complication rates can be encountered in any antihypertensive class mentioned, especially for RAS blockers and mineralocorticoid receptor inhibitors. This brief review aims to highlight the importance of diuretics use in CKD patients and the boundaries of their usage.

Aims To evaluate whether the addition of hydrochlorothiazide (HCTZ) to intravenous furosemide is a safe and effective strategy for improving diuretic response in acute heart failure (AHF). Methods and results A prospective, double-blind, placebo-controlled trial, including patients with AHF randomized to receive HCTZ or placebo in addition to an intravenous furosemide regimen. The coprimary endpoints were changes in body weight and patient-reported dyspnoea 72 h after randomization. Secondary outcomes included metrics of diuretic response and mortality/rehospitalizations at 30 and 90 days. Safety outcomes (changes in renal function and/or electrolytes) were also assessed. Two hundred and thirty patients (48 women, 83 years) were randomized. Patients assigned to HCTZ were more likely to lose weight at 72 h than those assigned to placebo [2.3 vs. 1.5 kg; adjusted estimated difference (notionally 95 confidence interval) 1.14 (1.84 to 0.42); P 0.002], but there were no significant differences in patient-reported dyspnoea (area under the curve for visual analogue scale: 960 vs. 720; P 0.497). These results were similar 96 h after randomization. Patients allocated to HCTZ showed greater 24 h diuresis (1775 vs. 1400 mL; P 0.05) and weight loss for each 40 mg of furosemide (at 72 and at 96 h) (P 0.001). Patients assigned to HCTZ more frequently presented impaired renal function (increase in creatinine 26.5 moL/L or decrease in eGFR 50; 46.5 vs. 17.2; P 0.001), but hypokalaemia and hypokalaemia were similar between groups. There were no differences in mortality or rehospitalizations. Conclusion The addition of HCTZ to loop diuretic therapy improved diuretic response in patients with AHF. [ABSTRACT FROM AUTHOR]

Background: Chronic hyponatremia is known to be associated with osteoporosis. It has been shown that chronic hyponatremia increases bone resorption in an attempt to release body stores of exchangeable sodium by different mechanisms. We wanted to know the calciuria of patients with hyponatremia of different origins. Material and Methods: We made a retrospective study of 114 consecutive patients with asymptomatic hyponatremia of different origins with the usual serum and urine chemistry. Result: In hyponatremia due to SIADH, we had a high urine calcium/creatinine ratio of 0.23 ± 0.096 while in patients with salt depletion the UCa/UCr ratio was low (0.056 ± 0.038), in patients with hyponatremia secondary to thiazide intake the value was also low (0.075 ± 0.047) as in hypervolemic patients (0.034 ± 0.01). In hyponatremia due to polydipsia, the value was high (0.205 ± 0.10). Correction of hyponatremia in the euvolemic patients was associated with a significant decrease in the UCa/UCr ratio. In patients with hyponatremia secondary to thiazide intake, we noted that in the patients with low uric acid levels (<4 mg/dL, suggesting euvolemia) we also observed a low UCa/UCr (<0.10). In nine patients with chronic SIADH (SNa 125.1 ± 3.6 mEq/L), the 24 h urine calcium excretion was 275 ± 112 mg and decreased to 122 ± 77 mg (p < 0.01) after at least 2 weeks of treatment. Conclusions: Patients with chronic hyponatremia due to SIADH usually have a high UCa/UCr ratio (>0.15). This is also observed in hyponatremia secondary to polydipsia. Patients with thiazide-induced hyponatremia usually have low UCa/UCr levels and this is the case even among those with a biochemistry similar to that in SIADH (uric acid < 4 mg/dL). [ABSTRACT FROM AUTHOR]

The thiazide class diuretics are first-line agents for managing hypertension either as monotherapy or as a fixed-dose combination with other antihypertensive drugs. However, despite the extensive experience with these drugs for >60 years, there is general reluctance to use these agents in patients with advanced chronic kidney disease (CKD) because of concerns about their efficacy and safety as kidney function declines. In this issue of Clinical Kidney Journal , Minutolo et al. performed an updated review of the pharmacological properties, efficacy and side effects and randomized controlled trials that tested these drugs in patients with CKD. [ABSTRACT FROM AUTHOR]

Sodium and volume excess is the fundamental risk factor underlying hypertension in chronic kidney disease (CKD) patients, who represent the prototypical population characterized by salt-sensitive hypertension. Low salt diets and diuretics constitute the centrepiece for blood pressure control in CKD. In patients with CKD stage 4, loop diuretics are generally preferred to thiazides. Furthermore, thiazide diuretics have long been held as being of limited efficacy in this population. In this review, by systematically appraising published randomized trials of thiazides in CKD, we show that this class of drugs may be useful even among people with advanced CKD. Thiazides cause a negative sodium balance and reduce body fluids by 1–2 l within the first 2–4 weeks and these effects go along with improvement in hypertension control. The recent CLICK trial has documented the antihypertensive efficacy of chlorthalidone, a long-acting thiazide-like diuretic, in stage 4 CKD patients with poorly controlled hypertension. Overall, chlorthalidone use could be considered in patients with treatment-resistant hypertension when spironolactone cannot be administered or must be withdrawn due to side effects. Hyponatremia, hypokalaemia, volume depletion and acute kidney injury are side effects that demand a vigilant attitude by physicians prescribing these drugs. Well-powered randomized trials assessing hard outcomes are still necessary to more confidently recommend the use of these drugs in advanced CKD. [ABSTRACT FROM AUTHOR]

Sulfonamide drugs paved the way for the antibiotic revolution in medicine. The sulfonamide chemical part is also present in other medications that are not antimicrobials, including thiazide diuretics, loop diuretics, anti-diabetic drugs, COX-2 inhibitors, etc. To make new derivatives of sulfa-drugs, test reactions by different synthetic procedures were performed to obtain Nbenzamidomethyl-4-toluenesulfonamide. By two different synthetic procedures, N-benzamidomethyl-4-toluenesulfonamide was obtained in high yields. Reaction) with 4-toluene sulfonamides and (benzamidomethyl)triethylammonium chloride were performed at room temperature in ethanol/water solutions (pH ≥ 9). The other synthetic method was performed in dichloromethane or water depending on the solubility of N-benzamidomethylamine. The structure of N-Benzamidomethyl -4-toluenesulfonamide was confirmed and characterized by IR, 1H–NMR, 13C–NMR, UV, and MS spectrometry. [ABSTRACT FROM AUTHOR]

Heart failure is an increasingly prevalent condition resulting in recurrent hospitalisations and significant mortality and morbidity. The management of heart failure has evolved, and multiple drugs have an established mortality benefit in heart failure with reduced ejection fraction. Although the focus should be on ensuring that patients are treated with the maximum tolerated doses of these guideline-directed therapies, diuretics continue to play a key role in the management of clinical congestion in all forms of heart failure. Clinicians play a key role in heart failure management. Familiarity with the role of diuretics and their dosing and monitoring is critical. [ABSTRACT FROM AUTHOR]

Glucocorticoid induced leucine zipper protein (GILZ) is an aldosterone-regulated protein that controls sodium transport in cultured kidney epithelial cells. Mice lacking GILZ have been reported previously to have electrolyte abnormalities. However, the mechanistic basis has not been explored. Here we provide evidence supporting a role for GILZ in modulating the balance of renal sodium and potassium excretion by regulating the sodium-chloride cotransporter (NCC) activity in the distal nephron. Gilz-/- mice have a higher plasma potassium concentration and lower fractional excretion of potassium than wild type mice. Furthermore, knockout mice are more sensitive to NCC inhibition by thiazides than are the wild type mice, and their phosphorylated NCC expression is higher. Despite increased NCC activity, knockout mice do not have higher blood pressure than wild type mice. However, during sodium deprivation, knockout mice come into sodium balance more quickly, than do the wild type, without a significant increase in plasma renin activity. Upon prolonged sodium restriction, knockout mice develop frank hyperkalemia. Finally, in HEK293T cells, exogenous GILZ inhibits NCC activity at least in part by inhibiting SPAK phosphorylation. Thus, GILZ promotes potassium secretion by inhibiting NCC and enhancing distal sodium delivery to the epithelial sodium channel. Additionally, Gilz-/- mice have features resembling familial hyperkalemic hypertension, a human disorder that manifests with hyperkalemia associated variably with hypertension.

Background: Previous findings on the associations of thiazide use with skin cancers were conflicting. This study aimed to examine the associations of individual thiazide use with skin cancer risk, differentiated by subtypes of skin cancers, geographic regions, and cumulative doses of individual thiazides.Methods: We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for relevant studies on January 5, 2022, scanned the references of included studies, and consulted experts. We included case-control and cohort studies or randomized trials reporting the associations of individual thiazide or thiazide-like diuretics use with skin cancers. Non-melanoma skin cancer (NMSC) and melanoma were analysed separately. A random-effects model meta-analysis was conducted for pooled odds ratio (OR) and hazard ratio (HR) for skin cancers related to individual thiazide use.Results: We included 15, 5, and 5 case-control or cohort studies reporting the risk for skin cancers associated with hydrochlorothiazide, bendroflumethiazide, and indapamide use, respectively, with 17,848,313 participants. The meta-analysis showed associations of hydrochlorothiazide use with increased risk of NMSC (OR 1.16, 95% CI 1.08-1.24; HR 1.26, 95% CI 1.04-1.54), squamous cell carcinoma (SCC) (OR 1.32, 95% CI 1.06-1.65; HR 1.61, 95% CI 0.97-2.67), and melanoma (OR 1.11, 95% CI 1.02-1.20; HR 1.03, 95% CI 0.93-1.14). The increased risks for SCC were associated with high cumulative doses of hydrochlorothiazide (OR 2.56, 95% CI 1.43-4.57; HR 1.20, 95% CI 1.00-1.45). Hydrochlorothiazide use was associated with different subtypes of melanoma including superficial spreading (OR 1.18, 95% CI 1.05-1.33), nodular (OR 1.23, 95% CI 1.08-1.39), and lentigo maligna melanoma (OR 1.33, 95% CI 1.08-1.65). Various cumulative doses of hydrochlorothiazide were associated with increased odds for melanoma. However, the associations of hydrochlorothiazide use with increased risk of NMSC and melanoma only appeared in non-Asian countries. No meaningful increase in the risk for skin cancers was associated with bendroflumethiazide and indapamide.Conclusions: Hydrochlorothiazide is associated with an increased risk for NMSC (especially SCC) and melanoma in non-Asian countries, whereas bendroflumethiazide and indapamide are not associated with a meaningful risk for skin cancers. Healthcare professionals and patients should be informed of the different risk profiles of skin cancers associated with different thiazides, cumulative doses, and regions.Trial Registration: PROSPERO CRD42021234317 . [ABSTRACT FROM AUTHOR]

A middle‐aged woman with a history of COVID‐19 vaccine administration and valve replacement surgery was admitted with bilateral palpable purpuric lesions in the lower extremities and headache. Based on the initial diagnosis of vasculitis, corticosteroid therapy was initiated, which led to the resolution of skin lesions. [ABSTRACT FROM AUTHOR]

Copyright of ScienceRise: Pharmaceutical Science is the property of PC TECHNOLOGY CENTER and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Background Hypokalemia is a common clinical problem. The association between urinary tract infection (UTI) and hypokalemia is not clear. Hypokalemia is common in patients with UTI in clinical observation. The aim of the study is to determine if UTI is associated with hypokalemia. Methods Patients hospitalized with UTI and the control group were retrieved from the Longitudinal Health Insurance Database 2005. The control group was patients hospitalized with other reasons and were matched for the confoundings of UTI and hypokalemia. We analyze the risk of hypokalemia using logistic regression and calculate the odds ratio (OR) and 95% confidence interval (CI) of OR. Results We analyzed 43,719 UTI patients and control patients. Hypokalemia was found in 4540 (10.4%) patients with UTI and 1842 (4.2%) control patients. The percentage of patients with hypokalemia was higher in UTI patients (chi-square, p

The article presents the consensus materials of the European Society of Cardiology on the use of diuretics in chronic heart failure (CHF). Diuretics represent an important class of drugs for the treatment of heart failure from the perspective of evidence based medicine. Much attention in the consensus s paid to the algorithm of using diuretics, in particular loop diuretics, in acute decompensation of CHF. Clinical and pharmacological advantages and disadvantages of the main drugs of loop diuretics (furosemide, torasemide, bumetanide) in CHF are discussed. There was analyzed the effectiveness of low and high doses of loop diuretics, the method of administration (bolus or continuous infusion) in terms of effective diuretic therapy and prevention of tolerance to diuretics, as well as the impact on the prognosis of survival during decompensation of heart failure. It also discusses modern approaches to the diagnostic criteria for assessing the effectiveness of diuretic therapy in acute decompensation of CHF, and shows the possibility of determination the level of excretion of Na+ ions in the urine as a surrogate marker of the effectiveness of diuretic therapy to optimize the dosage regimen of diuretics. An algorithm of diuretic therapy is proposed (the choice of dosages and regimens for using loop diuretics) for patients with acute decompensation of heart failure, including intravenous use of loop diuretics in an optimal increasing dose for the first 24 hours before stopping stagnation with a further transition to a maintenance dose of loop diuretic for euvolemia status and combined diuretic therapy with thiazides to obtain synergism. The recommendations for correction of electrolyte disturbances against the background of diuretic therapy is considered.Loop diuretics are recommended for CHF to prevent signs and symptoms of congestion: this is the only group of drugs with a level of recommendation as class I in patients with heart failure with a reduced or preserved ejection fraction.

Background: The addition of hydrochlorothiazide (HCTZ) to furosemide in the CLOROTIC (Combining Loop with Thiazide Diuretics for Decompensated Heart Failure) trial improved the diuretic response in patients with acute heart failure (AHF)., Objectives: This work aimed to evaluate if these results differ across the spectrum of left ventricular ejection fraction (LVEF)., Methods: This post hoc analysis of the randomized, double-blind, placebo-controlled CLOROTIC trial enrolled 230 patients with AHF to receive either HCTZ or a placebo in addition to an intravenous furosemide regimen. The influence of LVEF on primary and secondary outcomes was evaluated., Results: The median LVEF was 55%: 166 (72%) patients had LVEF >40%, and 64 (28%) had LVEF ≤40%. Patients with a lower LVEF were younger, more likely to be male, had a higher prevalence of ischemic heart disease, and had higher natriuretic peptide levels. The addition of HCTZ to furosemide was associated with the greatest weight loss at 72 of 96 hours, better metrics of diuretic response, and greater 24-hour diuresis compared with placebo, with no significant differences according to the LVEF category (using 2 LVEF cutoff points: 40% and 50%) or LVEF as a continuous variable (all P values were insignificant). There were no significant differences observed with the addition of HCTZ in terms of mortality, rehospitalizations, or safety endpoints (impaired renal function, hyponatremia, and hypokalemia) among the 2 LVEF groups (all P values were insignificant)., Conclusions: Adding HCTZ to intravenous furosemide seems to be effective strategy for improving diuretic response in AHF without treatment effect modification according to baseline LVEF. (Combining Loop with Thiazide Diuretics for Decompensated Heart Failure [CLOROTIC], NCT01647932; Randomized, double blinded, multicenter study, to asses Safety and Efficacy of the Combination of Loop With Thiazide-type Diuretics vs Loop diuretics with placebo in Patients With Decompensated, EudraCT Number 2013-001852-36)., Competing Interests: Funding Support and Author Disclosures This work was supported by the Heart Failure Working Group of the Spanish Society of Internal Medicine. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The Na-Cl cotransporter (NCC) is a well-recognized regulator of ion transportation in the kidneys that facilitates Na + reabsorption in the distal convoluted tubule. It is also the pharmacologic inhibitory target of thiazide diuretics, a class of front-line antihypertensive agents that have been widely used for decades. NCC is a potent regulator of Na + reabsorption and homeostasis. Hence, its overactivation and suppression lead to hypertension and hypotension, respectively. Genetic mutations that affect NCC function contribute to several diseases such as Gordon and Gitelman syndromes. We summarized the role of NCC in various physiologic processes and pathological conditions, such as maintaining ion and water homeostasis, controlling blood pressure, and influencing renal physiology and injury. In addition, we discussed the recent advancements in understanding cryo-EM structure of NCC, the regulatory mechanisms and binding mode of thiazides with NCC, and novel physiologic implications of NCC in regulating the cross-talk between the immune system and adipose tissue or the kidneys. This review contributes to a comprehensive understanding of the pivotal role of NCC in maintaining ion homeostasis, regulating blood pressure, and facilitating kidney function and NCC's novel role in immune and metabolic regulation., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

There is a growing recognition that children with Lowe syndrome are at risk of nephrocalcinosis and nephrolithiasis from hypercalciuria. Increased fluid intake and correction of metabolic acidosis have remained the focus for intervention but are not always successful. Thiazide diuretics, which reduce urinary calcium excretion, have not been used in these children, due to concerns that (i) they may not work as a result of the underlying tubular abnormalities and (ii) their risk may outweigh the potential benefits they have to offer. Herein we report a child with Lowe syndrome who was successfully treated with thiazides in managing his hypercalciuria.

Background In autosomal dominant polycystic kidney disease (ADPKD), hypertension is prevalent and cardiovascular events are the main cause of death. Thiazide diuretics are often prescribed as second-line antihypertensives, on top of renin–angiotensin–aldosterone system (RAAS) blockade. There is a concern, however, that diuretics may increase vasopressin concentration and RAAS activity, thereby worsening disease progression in ADPKD. We aimed to investigate the validity of these suggestions. Methods We analysed an observational cohort of 533 ADPKD patients. Plasma copeptin (surrogate for vasopressin), aldosterone and renin were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. Linear mixed models were used to assess the association of thiazide use with estimated glomerular filtration rate (eGFR) decline and Cox proportional hazards models for the association with the composite kidney endpoint of incident end-stage kidney disease, 40% eGFR decline or death. Results A total of 23% of participants (n  = 125) used thiazide diuretics at baseline. Compared with non-users, thiazide users were older, a larger proportion was male, they had lower eGFRs and similar blood pressure under more antihypertensives. Plasma copeptin was higher, but this difference disappeared after adjustment for age and sex. Both renin and aldosterone were higher in thiazide users. There was no difference between thiazide users and non-users in the rate of eGFR decline {difference −0.35 mL/min/1.73 m2 per year [95% confidence interval (CI) −0.83 to –0.14], P = 0.2} during 3.9 years of follow-up (interquartile range 2.5–4.9). This did not change after adjustment for potential confounders [difference final model: 0.08 mL/min/1.73 m2 per year [95% CI −0.46 to –0.62], P = 0.8). In the crude model, thiazide use was associated with a higher incidence of the composite kidney endpoint [hazard ratio (HR) 1.53 (95% CI 1.05–2.23), P = 0.03]. However, this association lost significance after adjustment for age and sex and remained unassociated after adjustment for additional confounders [final model: HR 0.80 (95% CI 0.50–1.29), P = 0.4]. Conclusions These data do not show that thiazide diuretics have a detrimental effect on the rate of disease progression in ADPKD and suggest that these drugs can be prescribed as second-line antihypertensives. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to determine the association between antihypertensive drug use and new-onset diabetes (NOD) in patients with hypertension (HTN). Materials and Methods: A retrospective observational study was conducted in a tertiary care hospital located in south India. Patients diagnosed with HTN and HTN with diabetes between January 2012 and December 2016, were identified and studied. Medical records of these patients from Medical Record Department were evaluated by medical record review method, and relevant data were recorded in a case record form. Statistical evaluation by chi-square method and odds ratio (OR) was carried out to appraise the incidence of NOD in patients taking antihypertensive medications. Results: A total of 1250 patients with HTN were screened, and based on inclusion and exclusion criteria, 952 patients were enrolled in the study; among which, 537 were patients with HTN and 415 were patients with diabetic HTN. The majority of the patients with HTN and patients with diabetic HTN were from the age-group of above 60 years. The most commonly prescribed drugs observed in our study population were amlodipine in 94 (22.7%) patients. OR was calculated and it was observed that the combination therapy has a fivefold risk for the development of NOD in patients with HTN, followed by Angiotensin II receptor blockers (2.06) (confidence interval [CI]: 1.56–2.73), diuretics (1.33) (CI: 0.95–1.85), non-Dihydropyridine calcium channel blockers (DHP CCBs) (1.3) (CI: 0.51–3.30), vasodilators (1.13) (CI: 0.40–3.15), and Angiotensin converting enzyme inhibitors (1.06) (0.68–1.64). Conclusion: Patients on non-DHP CCBs, diuretics, and combination antihypertensives showed more chances of developing NOD.

Abstract Background Thiazide diuretics have demonstrated favorable blood pressure lowering efficacy, but the equivalent doses of their more common agents, chlorthalidone and hydrochlorothiazide, are still unclear. Further, concerns exist regarding adverse metabolic effects, which may be attenuated with the concomitant administration of a potassium-sparing diuretic, such as amiloride. This trial aims to investigate the efficacy of chlorthalidone and hydrochlorothiazide, in combination with amiloride at different doses, for initial management of patients with primary hypertension. Methods/design This is a factorial (2 × 2) randomized double-blinded clinical trial comparing the association of a thiazide diuretic (chlorthalidone 25 mg/day or hydrochlorothiazide 50 mg/day) with a potassium-sparing diuretic (amiloride 10 mg/day or amiloride 20 mg/day) in patients with primary hypertension. The primary outcome will be the mean change from baseline in 24-h systolic and diastolic blood pressure measured by ambulatory blood pressure monitoring. The secondary outcomes will be the mean change from baseline in daytime and nighttime systolic and diastolic blood pressure measured by ambulatory blood pressure monitoring, mean change from baseline in systolic and diastolic blood pressure measured by office blood pressure, incidence of adverse events, variation of laboratory parameters, and proportion of patients who achieved blood pressure control. The follow-up will last 12 weeks. For a P alpha of 0.05, power of 80%, standard deviation of 9 mmHg, and absolute difference of 6 mmHg on systolic blood pressure on 24-h ambulatory blood pressure monitoring, it will be necessary to study a total of 76 patients. The sample size will be increased by 10% to compensate for losses, resulting in 84 patients being randomized. Discussion Diuretics are pivotal drugs for the treatment of hypertension. Chlorthalidone and hydrochlorothiazide, in combination with amiloride in multiple doses, will be tested in terms of blood pressure lowering efficacy and safety. Since the intensity of blood pressure reduction is the major determinant of reduction in cardiovascular risk in hypertensive patients, this study will help to determine which combination of diuretics represents the most appropriate treatment for this population. Trial registration ClinicalTrials.gov, NCT03928145. Registered on 25 April 2019. Last update on 29 April 2019.

Abstract Background Stroke is a major risk factor for osteoporosis and fractures. No study has evaluated the association between diuretic use and risk of vertebral fracture in stroke patients, although a considerable proportion of stroke patients are prescribed diuretics for hypertension. Our study aimed to investigate whether treatment with thiazides or loop diuretics affects the risk of vertebral fracture after stroke. Methods A population-based propensity score-matched retrospective cohort study was conducted using the Taiwan National Health Insurance Research Database. Patients with a new diagnosis of stroke between 2000 and 2011 were included. After propensity score matching, 9468 patients were included in the analysis of the effect of thiazides, of who 4734 received thiazides within 2 years after stroke. To analyze the loop diuretic effect, 4728 patients were included, of who 2364 received loop diuretics. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) of vertebral fractures among patients according to thiazide or loop diuretic use within 2 years following stroke. Sensitivity analyses based on the duration of thiazide or loop diuretic use were further conducted. Results There was no significant difference in vertebral fracture risk between thiazide users and non-users (adjusted HR [aHR] = 1.14, 95% confidence interval [CI] = 0.88–1.47, p = 0.316). Loop diuretic users had a significantly higher vertebral fracture risk than non-users (aHR = 1.45, 95% CI = 1.06–1.98, p = 0.019). However, the sensitivity analysis revealed that short-term thiazide use (exposure duration