Combinational Diuretics in Heart Failure.

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. 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.

Combining loop with thiazide diuretics for decompensated heart failure: the CLOROTIC trial.

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.

Effectiveness of thiazide and thiazide-like diuretics in advanced chronic kidney disease: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: 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. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 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. RESULTS: 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. CONCLUSION: 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.

Associations of thiazide use with skin cancers: a systematic review and meta-analysis.

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 .

Diuretics in the management of chronic heart failure: when and how.

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.

What Dermatologists Should Know About Thiazides. / Tiazidas: lo que el dermatólogo debería saber.

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.

The Forgotten Antiproteinuric Properties of Diuretics.

BACKGROUND: Although diuretics are one of the most widely used drugs by nephrologists, their antiproteinuric properties are not generally taken into consideration. SUMMARY: Thiazide diuretics have been shown to reduce proteinuria by >35% in several prospective controlled studies, and these values are markedly increased when combined with a low-salt diet. Thiazide-like diuretics (indapamide and chlorthalidone) have shown similar effectiveness. The antiproteinuric effect of mineralocorticoid receptor antagonists (spironolactone, eplerenone, and finerenone) has been clearly established through prospective and controlled studies, and treatment with finerenone reduces the risk of chronic kidney disease progression in type-2 diabetic patients. The efficacy of other diuretics such as amiloride, triamterene, acetazolamide, or loop diuretics has been less explored, but different investigations suggest that they might share the same antiproteinuric properties of other diuretics that should be evaluated through controlled studies. Although the inclusion of sodium-glucose cotransporter-2 inhibitors (SGLT2i) among diuretics is a controversial issue, their renoprotective and cardioprotective properties, confirmed in various landmark trials, constitute a true revolution in the treatment of patients with kidney disease. Recent subanalyses of these trials have shown that the early antiproteinuric effect induced by SGLT2i predicts long-term preservation of kidney function. Key Message: Whether the early reduction in proteinuria induced by diuretics other than finerenone and SGLT2i, as summarized in this review, also translates into long-term renoprotection requires further prospective and observational studies. In any case, it is important for the clinician to be aware of the antiproteinuric properties of drugs so often used in daily clinical practice.

Association between newly initiated thiazide diuretics and hospitalization due to hyponatremia.

PURPOSE: Thiazide diuretics are the most common origin of drug-induced hyponatremia. However, population-based studies on clinical outcomes are lacking. We therefore explored the time course and absolute risk of thiazide-associated hospitalization due to hyponatremia in Sweden. METHODS: Population-based case-control study including patients hospitalized with a principal diagnosis of hyponatremia (n = 11,213) compared with controls (n = 44,801). Linkage of registers was used to acquire data. Multivariable regression was applied to explore time-dependent associations between thiazide diuretics and hospitalization due to hyponatremia. Attributable risks were calculated assessing the disease burden attributable to thiazides. RESULTS: Individuals initiating thiazide treatment were exposed to an immediate increase in risk for hospitalization with adjusted odds ratio (aOR) (95% CI) of 48 (28-89). The associations gradually declined reaching an aOR of 2.9 (2.7-3.1) for individuals treated for longer than 13 weeks. The attributable risk of hyponatremia-associated hospitalization due to thiazides of any treatment length was 27% (3095/11,213). Among 806 patients initiating treatment < 90 days before hospitalization, hyponatremia could be attributed to thiazides in 754. Based on nationwide data, 616,678 individuals were initiated on thiazides during the 8-year study period suggesting an absolute risk of 0.12% (754/661,678) for subsequent hospitalization with a main diagnosis of hyponatremia. CONCLUSIONS: Thiazide diuretics attributed to more than one in four individuals hospitalized due to hyponatremia. The risk increase was very pronounced during the first month of treatment and then gradually declined, without returning to normal. However, the absolute risk for the development of hyponatremia demanding hospitalization may for most individuals be modest.

SGLT2 inhibitors and thiazide enhance excretion of DEHP toxic metabolites in subjects with type 2 diabetes: A randomized clinical trial.

OBJECTIVE: Phthalates are non-persistent pollutants related to impaired metabolism and high cardiovascular risk. Their toxic metabolites are eliminated through urine and feces. Prevention policies are considered by the governments, although no therapeutic strategy to facilitate their elimination from the human body has been proposed so far. Aim of the present study was to verify, for the first time in humans, whether diuretics might be able to enhance phthalates' toxic metabolites urinary output. DESIGN AND METHODS: We conducted a two-armed, parallel-design, randomized clinical trial. Thirty patients with type 2 diabetes and hypertension received a four week-treatment with Dapagliflozin 10 mg or Hydrochlorothiazide 12.5 mg. 24-hours urine were collected to measure urinary excretion of three major 2-ethylhexyl-phthalate (DEHP) metabolites, i.e. mono 2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) and mono 2-ethyl-5-hydroxyhexyl phthalate (MEHHP). RESULTS: 24-h urinary excretion of DEHP and MEHP was increased (+44%, p = 0.036; +49%, p = 0.0016) while MEOHP e MEHHP showed only a positive trend (+25%, p = 0.016; +36%, p = 0.062). Irrespective of the specific treatment, induced variations of daily urinary eliminations of MEHP metabolites were related with the 24-h urinary sodium (r = 0.42, p = 0.0226) and potassium (r = 0.54, p = 0.0026) excretion. Also, DEHP and MEOHP were related to sodium (r = 0·43, p = 0.0205; r = 0·44, p = 0.0168 respectively) but not to potassium. CONCLUSIONS: Urinary phthalates excretion seems to occur mainly through sodium- and potassium-related mechanisms, apparently independent from the different diuretic effect. Both thiazide diuretics and SLGT2 inhibitors are effective into the removal of phthalates metabolites from the human body, reducing the human tissues' exposure to their toxicity.

[Diuretics as a problem-Pharmacokinetics, pharmacodynamics, use in edema or hypertension]. / Diuretika als Problem ­ Pharmakokinetik und -dynamik, Einsatz bei Ödemen oder Hypertonie.

BACKGROUND AND OBJECTIVE: Diuretics are key elements of the pharmacotherapy of diseases in internal medicine. Currently, they are particularly used in the treatment of edema and hypertension. For the treatment with diuretics some rules exist that help to improve the effectiveness and success. The article explains these rules, especially regarding combination treatment and meaningful dose escalation. Additionally, the side effects of treatment are critically discussed. RESULTS AND CONCLUSION: There is little evidence for the influence of diuretics in the treatment of edema on prognostic factors, such as mortality and comorbidities. For an improvement of the prognosis other substances are more important, e.g. angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers; however, diuretics in the treatment of hypertension show clear positive effects on the endpoints. In recent years a problem of side effects was demonstrated (skin cancer). Comparing the benefits regarding prognosis in the treatment of hypertension with the side effects, the administration but with appropriate protective measures seems to be warranted.

Urinary tract infection is associated with hypokalemia: a case control study.

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 < 0.001). UTI was associated with hypokalemia and the odds ratio (OR) was 2.27 [95% confidence interval (CI): 2.17-2.41]. Cerebrovascular accident, chronic obstructive pulmonary disease, hypertension, congestive heart failure, diarrhea, medications including thiazides, sulfonamides, xanthines, and laxatives were independently associated with hypokalemia. Recurrent UTI was associated with hypokalemia in UTI patients (OR: 1.13, 95% CI: 1.05-1.23, p < 0.001). CONCLUSIONS: Urinary tract infection is associated with hypokalemia among inpatients. The association is independent of patients' comorbidities and medications. Recurrent UTI is associated with increased hypokalemia in UTI patients.

Intriguing relationship between antihypertensive therapy and cancer.

Arterial hypertension is the most frequent cardiovascular risk factor in the cancer patients. Anti-cancer therapy very often induces arterial hypertension and the treatment with antihypertensive medications is inevitable. Additionally, anti-cancer therapy frequently induces cardiotoxicity that has been treated or even could be prevented by use of antihypertensive medications - primarily angiotensin converting enzyme inhibitors and beta-blockers. The association between antihypertensive drugs and cancer is matter of large debate in the last several years because of the conflicting results from available studies ranging from adverse to beneficial effect of various antihypertensive classes. The mechanisms of the relationship between antihypertensives and cancer are still in domain of hypothesis. Some studies described the association between different antihypertensive groups and malignancies. There are investigations that denied negative effects of antihypertensive medications on cancer occurrence, recurrence, cancer-related complications and mortality. On the other hand, there are researches that reported a beneficial effect of antihypertensive medication by decreasing mortality in the cancer patients. One should be aware of the discrepancy of investigated antihypertensives in these researches and heterogeneity of included patients - different age, cancer type, comorbidities, demographic characteristics, and anti-cancer therapy. This comprehensive review article aimed to summarize the current knowledge regarding the relationship between antihypertensive medications and cancer.

Idiopathic Generalized Exfoliative Dermatitis and Association with Antihypertensive Drugs and Statins: A Retrospective Case-Control Study.

BACKGROUND/AIMS: We aim to examine the hypothesis that antihypertensive drugs and statins may be responsible for the development of idiopathic generalized exfoliative dermatitis (GED) with a case-control study. METHODS: All inpatients who were hospitalized under the dermatology service at the Tan Tock Seng Hospital, Singapore, between 1 May 2013 and 31 May 2015, were analysed. Idiopathic GED cases had consistent clinical and histological features but no apparent cause despite comprehensive evaluation. Controls were randomly selected from inpatients with other dermatological conditions in a 1: 1 ratio during the same period. Their relationship was analysed using univariate (χ2 or Fisher exact tests) and multivariate logistic regression analysis. RESULTS: There were 78 cases and 83 controls. Of the 78 cases, 42 patients had a history of treatment with antihypertensive drugs or statins. Cases were not found to be more likely on angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, ß-blockers, calcium channel blockers, thiazides or statins compared to controls (OR: 0.81; 95% CI: 0.43-1.51; p = 0.507). CONCLUSIONS: There was insufficient evidence to suggest a significant relationship between the chronic use of antihypertensive drugs or statins and idiopathic GED in this study, despite previous evidence reporting this might be so. Further case-control studies with larger sample sizes are needed to evaluate this association.

Hydrochlorothiazide-induced photosensitivity in a psoriasis patient following exposure to narrow-band ultraviolet B excimer therapy.

Drug-induced photosensitivity develops when the use of oral or topical photosensitizing medications creates a rash after exposure to ultraviolet (UV) radiation. Medications most commonly implicated in photosensitive drug reactions include amiodarone, nonsteroidal anti-inflammatories, thiazides, tetracycline antibiotics, chlorpromazine, and fluoroquinolones. It is generally believed that drug-induced photosensitivity is an UVA phenomenon, caused by UV wavelengths between 315 and 400 nm. Here, we present a case of hydrochlorothiazide (HCTZ)-induced photosensitivity following exposure to 308-nm narrow-band (nb) UVB light emitted from an excimer laser in a patient undergoing treatment for plaque psoriasis. This patient had received biweekly treatments with the excimer laser for years prior without any history of adverse reactions. We believe that our patient suffered an acute photosensitivity to UVB due to new-onset HCTZ. Because nb UVB-emitting lasers are used to treat many dermatologic conditions, physicians should be aware of potential photosensitivity reactions, review medication lists and counsel patients accordingly.

Structure-function relationships in the renal NaCl cotransporter (NCC).

The thiazide-sensitive Na+-Cl- cotransporter (NCC) is the major pathway for salt reabsorption in the distal convoluted tubule, serves as a receptor for thiazide-type diuretics, and is involved in inherited diseases associated with abnormal blood pressure. The functional and structural characterization of NCC from different species has led us to gain insights into the structure-function relationships of the cotransporter. Here we present an overview of different studies that had described these properties. Additionally, we report the cloning and characterization of the NCC from the spiny dogfish (Squalus acanthias) kidney (sNCC). The purpose of the present study was to determine the main functional, pharmacological and regulatory properties of sNCC to make a direct comparison with other NCC orthologous. The sNCC cRNA encodes a 1033 amino acid membrane protein, when expressed in Xenopus oocytes, functions as a thiazide-sensitive Na-Cl cotransporter with NCC regulation and thiazide-inhibition properties similar to mammals, rather than to teleosts. However, the Km values for ion transport kinetics are significantly higher than those observed in the mammal species. In summary, we present a review on NCC structure-function relationships with the addition of the sNCC information in order to enrich the NCC cotransporter knowledge.

Association between diuretic use and the risk of vertebral fracture after stroke: a population-based retrospective cohort study.

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 < 90 days within 2 years after stroke) significantly increased the risk of vertebral fracture versus non-use (aHR = 1.38, 95% CI = 1.02-1.88, p = 0.039). Only short-term loop diuretic users had significantly higher risk of vertebral fracture (aHR = 1.56, 95% CI = 1.11-2.20, p = 0.011). The other two subgroups with longer exposure duration in analyses for both thiazides and loop diuretics revealed no significant effect. CONCLUSIONS: Short-term thiazide or loop diuretic use was associated with an increased risk of vertebral fracture after stroke. Further prospective clinical trials are required to confirm this finding.

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.

The Art and Science of Using Diuretics in the Treatment of Heart Failure in Diverse Clinical Settings.

It is important to understand the rationale for appropriate use of different diuretics, alone or in combination, in different heart failure patients, under diverse clinical settings. Clinicians and nurses engaged in heart failure care, must be familiar with different diuretics, their appropriate doses, methods of administration, monitoring of the responses, and the side-effects. Inappropriate use of diuretics, both under-treatment and overtreatment, and poor follow-up can lead to failures, and adverse outcomes. Adequate treatment of congestion, with rather aggressive use of diuretics, is necessary, even if that may worsen renal function temporarily in some patients. Diuretic treatment should later be titrated down, by early recognition of the euvolemic sate, which can be assessed by clinical examination, measurement of the natriuretic peptides, and when possible, echocardiographic estimation of the left ventricular filling pressure. You need to treat patients, who are truly resistant to the loop diuretics, by administering the diuretics as intravenous bolus injection followed by continuous infusion, and/or by sequential nephron blockade by adding the thiazide diuretics. You need to use the diuretics based on a sound understanding of the pathophysiology of the disease process, the pharmacokinetics and pharmacodynamics of the diuretics, even when strong evidences for your choices might be lacking. Some patients may benefit from injection of loop diuretics together with hypertonic saline, and others from injection of loop diuretics with albumin. Patient education, and regular follow up of the treatment of heart failure patients, in out-patient settings are important for reducing the rates of complications, and for reducing the needs for urgent hospitalizations.

The Effects of Diuretics on Mineral and Bone Metabolism.

The effects of diuretics on water and electrolyte metabolism are well-established, but less known to the clinician are their effects on bone and mineral metabolism, and in particular on that of calcium homeostasis. In general, and clinically most relevant, diuretics acting at the thick ascending limb of the loop of Henle cause loss of calcium into the urine, thus making them a useful tool in treating hypercalcemia. However the hypercalciuria caused by loop diuretics may lead to the development of urolithiasis and nephrocalcinosis, as well as secondary hyperparathyroidism and bone disease. On the other hand, thiazide diuretics that act more distally, increase tubular calcium reabsorption, thus providing protection against hypercalciuria, and with that may raise serum calcium, suppress PTH secretion and improve bone metabolism. Additional hypocalciuric effect may be observed with the use of potassium-sparing diuretics. This review will address the effects of diuretics on mineral metabolism in the kidney and consequently on systemic mineral and bone metabolism.