Classes Of Diuretics Research Articles

Protective Effects of Diuretics Against the Development of Cardiovascular Disease in Patients with Chronic Kidney Disease: A Systematic Review.

Cardiovascular disease is one of the most important risk factors for mortality and morbidity in patients with Chronic Kidney Disease (CKD). This systematic review focuses on the protective effects of diuretics against the development of cardiovascular disease in patients with CKD. Among various kinds of diuretics, spironolactone, a mineralocorticoid receptor antagonist, has been shown to have protective effects against cardiovascular disease in patients with all stages of CKD, including predialysis, hemodialysis, and peritoneal dialysis. Low-dose loop diuretics have also been shown to have cardioprotective effects in patients with CKD during the pre-dialysis and hemodialysis stages; however, high-dose loop diuretics have failed to show these cardioprotective effects. The protective effects of other classes of diuretics, including thiazide and tolvaptan, against cardiovascular diseases in patients with CKD remain unclear.

Mode of death and predictors of mortality in adult Fontan survivors: A Japanese multicenter observational study

BackgroundMortality rates may be high in adult Fontan patients; however, the clinical determinants remain unclear. PurposeWe conducted a prospective multicenter study of adult Fontan survivors to determine the 5-year mortality rate and clarify the determinants. Method and resultsWe followed 600 adult Fontan survivors from 40 Japanese institutions (307 men, 28 ± 7 years old, follow-up: 18 ± 6 years). The New York Heart Association (NYHA) functional class I and II was 51% and 42%, respectively. During the follow-up period of 4.1 ± 1.6 years, 33 patients died, and the 5-year survival rate was 93.5%. The mode of death was heart failure in 11 patients (34%), arrhythmia or sudden death in 8 (24%), cancer in 5 (15%), perioperative problems and hemostatic problems in 4 each (12% for each), and infection in 1 (3%). Left isomerism, prior hospitalization, protein losing enteropathy (PLE), pulmonary arteriovenous fistulae, NYHA functional class, impaired hemodynamics, hyponatremia, hepatorenal dysfunction, and use of diuretics were associated with a high mortality rate (p < 0.05–0.0001). Further, PLE (hazard ratio [HR]: 14.4), left isomerism (HR: 3.5), and NYHA (HR: 2.4) independently predicted a high 5-year high mortality (p < 0.05 for all). The incidence of cancer-related mortality increased markedly with age >40 years. ConclusionsMajority of the Japanese adult Fontan survivors had good functional status, with an acceptable 5-year survival rate. However, the significant prevalence of non-cardiac mortality highlights Fontan pathophysiology as a multi-organ disease that requires a multidisciplinary management strategy to improve the long-term outcome.

Preclinical evaluation of the diuretic and saluretic effects of (-)-epicatechin and the result of its combination with standard diuretics

Several studies have suggested that (-)-epicatechin-containing foods and plant extracts benefit conditions that affect the cardiovascular system, such as hypertension and endothelial dysfunction. However, no study was conducted so far to evaluate the potential of this flavonoid on diuretic activity assay. For that, female Wistar normotensive (NTR) and spontaneously hypertensive rats (SHR) received a single oral treatment with (-)-epicatechin (EPI), hydrochlorothiazide (HCTZ) or just vehicle (VEH). The effects of EPI in combination with diuretics for clinical use, as well as with L-NAME, atropine and indomethacin were also explored. Cumulative urine volume, plasma and urinary parameters were evaluated at the end of 8 h experiment. When given to NTR and SHR, at doses of 0.3, 1 and 3 mg/kg, EPI was able to stimulate both diuresis and saluresis (Na+, K+ and Cl−), without interfering with plasma electrolyte content or urinary pH and uric acid values, when compared with VEH-treated only rats. The combination with HCTZ, but not with furosemide or amiloride, successfully strengthened EPI-induced diuresis. This effect was not accompanied by a potentiation of the saluretic effects. On the other hand, when given EPI in combination with amiloride, a significant increase in Cl− excretion and maintenance of the potassium-sparing effects characteristic of this class of diuretics were detected. In addition, the diuretic effect of EPI was enhanced after pretreatment with L-NAME and its action was significantly precluded in the presence of indomethacin, a cyclooxygenase inhibitor. In conclusion, this study shows the diuretic and saluretic properties of EPI in rats, adding another biological activity whose effect may contribute to the different positive actions already described.

Antihyperglycemic agents as novel natriuretic therapies in diabetic kidney disease.

While sodium-glucose cotransporter-2 (SGLT2) inhibitors have been used for the routine management of type 2 diabetes for several years, it is perhaps their natriuretic effects that are most important clinically. This natriuresis activates tubuloglomerular feedback, resulting in reduced glomerular hypertension and proteinuria, leading to renal protective effects in the EMPA-REG OUTCOME and CANVAS Program trials. In the cardiovascular system, it is likely that plasma volume contraction due to natriuresis in response to SGLT2 inhibition is at least in part responsible for the reduction in the risk of heart failure observed in these trials. We compare this mechanism of action with other antidiabetics. Importantly, other diuretic classes, including thiazide and loop diuretics, have not resulted in such robust clinical benefits in patients with type 2 diabetes, possibly because these older agents do not influence intraglomerular pressure directly. In contrast, SGLT2 inhibitors do have important physiological similarities with carbonic anhydrase inhibitors, which also act proximally, and have been shown to activate tubuloglomerular feedback.

The Renal Outer Medullary Potassium Channel (ROMK): An Intriguing Pharmacological Target for an Innovative Class of Diuretic Drugs.

In the last four decades, the several classes of diuretics, currently available for clinical use, have been the first line option for the therapy of widespread cardiovascular and non-cardiovascular diseases. Diuretic drugs generally exhibit an overall favourable risk/benefit balance. However, they are not devoid of side effects. In particular, all the classes of diuretics cause alteration of potassium homeostasis. In recent years, understanding of the physiological role of the renal outer medullary potassium (ROMK) channels, has shown an intriguing pharmacological target for developing an innovative class of diuretic agents: the ROMK inhibitors. This novel class is expected to promote diuretic activity comparable to (or even higher than) that provided by the most effective drugs used in clinics (such as furosemide), with limited effects on potassium homeostasis. In this review, the physio-pharmacological roles of ROMK channels in the renal function are reported, along with the most representative molecules which have been currently developed as ROMK inhibitors.

ESTUDOS DE EQUIVALÊNCIA FARMACÊUTICA E PERFIL DE DISSOLUÇÃO COMPARATIVO DE MEDICAMENTOS CONTENDO HIDROCLOROTIAZIDA

A hidroclorotiazida (HCTZ) é um fármaco da classe dos diuréticos tiazídicos, amplamente utilizado no tratamento de pacientes com edema e hipertensão arterial sistêmica leve a moderada, sendo considerado altamente efetivo pelos profissionais da saúde. O objetivo deste trabalho foi avaliar a equivalência farmacêutica e realizar estudos comparativos de perfil de dissolução entre medicamento Referência (R) e três medicamentos Genéricos (G1, G2 e G3) na forma de comprimidos de liberação imediata de HCTZ (25 mg), de acordo com a monografia apresentada na Farmacopeia Brasileira 5ª Ed. (2010) e a legislação nacional vigente. Nos testes físicos e físico-químicos todos os medicamentos G foram aprovados, no entanto, em alguns casos apresentaram diferenças significativas quando comparados ao medicamento R. Em relação ao perfil de dissolução, o qual visa avaliar o fator de semelhança F2, apenas o medicamento G3 não apresentou um perfil semelhante quando comparado ao medicamento R. A intercambialidade entre G3 e R pode estar comprometida, pois há possibilidade de não atingir níveis plasmáticos da HCTZ na velocidade e extensão desejadas. Os resultados deste trabalho podem refletir a qualidade e confiabilidade dos medicamentos genéricos amplamente utilizados pela população brasileira.

Discovery, characterization, and preclinical development of a Kir4.1 (KCNJ10) inhibitor for the treatment of hypertension

Kir4.1 (encoded by KCNJ10) inward rectifier potassium channels are emerging as key regulators of sodium reabsorption in the distal nephron of the kidney. Kir4.1 is expressed in the basolateral membrane of the thick ascending limb of Henle, distal convoluted tubule, and collecting duct of nephron. Kir4.1 can form homotetrameric channels or heterotetrameric channels with Kir5.1, although the most common channel subtype in the kidney is the heteromeric Kir4.1/5.1 form. Genetic ablation of Kir4.1 in mice or humans causes severe salt and water wasting resembling clinical phenotypes associated with diuretic use. These human validation data and recent animal studies suggest that Kir4.1 might represent a novel diuretic target for the management of hypertension through inhibition of distal nephron sodium reabsorption. The aim of this study was to develop a selective small‐molecule inhibitor for evaluating the therapeutic potential of renal Kir4.1 channels. From a high‐throughput screen of 76,575 compounds from the Vanderbilt Institute of Chemical Biology library, we identified an inhibitor, termed VU992, which inhibits homotetrameric Kir4.1 with an IC50 of ~0.9 μM and heterotetrameric Kir4.1/5.1 with an IC50 of ~ 9 μM. Lead optimization failed to identify analogs with improved potency toward Kir4.1. The selectivity screening against other Kir channels revealed that VU992 does not block Kir1.1, Kir2.x, Kir6.1/SUR1 and Kir7.1 channels. The voltage dependent unblock suggested that VU992 probably binds in the pore of the Kir4.1 channel. Computational docking analysis using a Kir4.1 homology model revealed several possible interacting residues in the pore. Experimental binding site analysis using mutagenesis and patch clamp electrophysiology suggested that the pore lining glutamic acid residue at 158 (E158) is crucial for the binding of VU992 to the Kir4.1. Mutating E158 to corresponding asparagine residue in Kir1.1 (E158N) abolished the VU992 block completely. Pharmacokinetic studies in rats showed that VU992 does not cross the blood brain barrier and therefore should not inhibit Kir4.1 channels expressed in the CNS. Finally, oral administration of VU992 dose‐dependently increased urine output and Na+ and K+ loss in volume‐loaded, freely behaving rats. This study shows proof‐of‐concept that homotetrameric Kir4.1 might represent a molecular target for a novel class of diuretic for the treatment of hypertension. Its basolateral localization might offer advantages over other diuretic targets that are located on the luminal membrane of the nephron.Support or Funding InformationNIH 5R21 NS073097‐01S1This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis.

The effect of a sodium glucose cotransporter 2 inhibitor (SGLT2i) in reducing heart failure hospitalization in the EMPA-REG OUTCOMES trial has raised the possibility of using these agents to treat established heart failure. We hypothesize that osmotic diuresis induced by SGLT2 inhibition, a distinctly different diuretic mechanism than that of other diuretic classes, results in greater electrolyte-free water clearance and, ultimately, in greater fluid clearance from the interstitial fluid (IF) space than from the circulation, potentially resulting in congestion relief with minimal impact on blood volume, arterial filling and organ perfusion. We utilize a mathematical model to illustrate that electrolyte-free water clearance results in a greater reduction in IF volume compared to blood volume, and that this difference may be mediated by peripheral sequestration of osmotically inactive sodium. By coupling the model with data on plasma and urinary sodium and water in healthy subjects who received either the SGLT2i dapagliflozin or loop diuretic bumetanide, we predict that dapagliflozin produces a 2-fold greater reduction in IF volume compared to blood volume, while the reduction in IF volume with bumetanide is only 78% of the reduction in blood volume. Heart failure is characterized by excess fluid accumulation, in both the vascular compartment and interstitial space, yet many heart failure patients have arterial underfilling because of low cardiac output, which may be aggravated by conventional diuretic treatment. Thus, we hypothesize that, by reducing IF volume to a greater extent than blood volume, SGLT2 inhibitors might provide better control of congestion without reducing arterial filling and perfusion.

Diuretic treatment in patients with chronic heart failure: evidences, experiences, and current perspectives

Congestion is a fundamental clinical sign in patients with chronic heart failure (CHF). Diuretics are the mainstay treatment for congestion but, so far, no randomized trial has ever shown any beneficial effect of diuretics on mortality in patients with CHF. It is also unclear how and when diuretics should be up, or down titrated, or when their use can be safely stopped. In this review, we discuss current evidence regarding the clinical use of diuretics. We also highlight the need for more clinical trials to explore the short- and long-term safety, efficacy and clinical benefits of different classes of diuretics, used alone or in combination, in patients with CHF.

Clinical Associations of Early Dysnatremias in Critically Ill Neonates and Infants Undergoing Cardiac Surgery.

subjects that demonstrated DN before surgery. Serum sodium levels were recorded for the first 72h post-operatively. DN was present in 54% of the subjects (98/183): hypernatremia in 60 (33%), hyponatremia in 38 (21%). Multivariate analysis revealed that mild hypernatremia (146-150mmol/dl) and moderate hypernatremia (151-155mmol/dl) were associated with longer hospital length of stay (LOS, p<0.05) and ventilation times (p<0.05). No association was shown between mild/moderate hyponatremia (125-134mmol/dl) with either outcome. Hours to DN were significantly lower in hypernatremic (median=5.8h) than hyponatremic (median=43.8h) patients (p<0.001). Children younger than 30days presented DN at an earlier stage than those 31days-1year old (median +2.2 vs. 17.3h). No associations present between DN and the class of diuretic (loop vs. thiazide) administered, or the route of administration (intravenous bolus vs. constant infusion). Total median sodium bicarbonate administration was associated with hypernatremia, as was exposure to vasopressin within the first 72h post-operatively. Dysnatremias are common in the early post-operative period in neonates and infants undergoing cardiac surgery. Mild to moderate hypernatremia, but not hyponatremia, is associated with longer LOS and longer ventilation time in infants undergoing cardiovascular surgery. Hypernatremia is also associated with younger infants, a higher surgical complexity, administration of bicarbonate and exposure to vasopressin. Diuretic type or interval timing of intravenous delivery did not demonstrate any effect. Prospective studies are needed in this population, in order to determine how DN, particularly hypernatremia, contributes to adverse outcomes, whether this association is independent of illness severity, and what may be safe treatments and interventions for these disorders.

8-Aminoguanosine and 8-Aminoguanine Exert Diuretic, Natriuretic, Glucosuric, and Antihypertensive Activity.

In vivo, guanine moieties in DNA, RNA, guanine nucleotides, or guanosine or guanine per se can undergo nitration (for example, by peroxynitrite) or hydroxylation (for example, by superoxide anion) on position 8 of the purine ring. Subsequent catabolism of these modified biomolecules leads to the production of a diverse group of 8-nitro, 8-amino, and 8-hydroxy guanosine and guanine compounds. Indeed, studies suggest the in vivo existence of 8-nitroguanosine, 8-nitroguanine, 8-aminoguanosine, 8-aminoguanine, 8-hydroxyguanosine, 8-hydroxy-2'-deoxyguanosine, and 8-hydroxyguanine. Since a multitude of these compounds exist in vivo, and since the renal effects of 8-substituted guanosine and guanine compounds are entirely unknown, we examined the effects of guanosine, guanine, 8-nitroguanosine, 8-nitroguanine, 8-hydroxyguanosine, 8-hydroxyguanine, 8-hydroxy-2'-deoxyguanosine, 8-aminoguanosine, and 8-aminoguanine (33.5 µmol/kg/min; intravenous infusion for 115 minutes) on excretion of sodium, potassium, and glucose in rats. Guanosine, 8-nitroguanosine, and 8-hydroxy-2'-deoxyguanosine had minimal natriuretic activity. Guanine, 8-nitroguanine, 8-hydroxyguanosine, and 8-hydroxyguanine had moderate natriuretic activity (increased sodium excretion by 9.4-, 7.8-, 7.1-, and 8.6-fold, respectively). In comparison with all other compounds, 8-aminoguanosine and 8-aminoguanine were highly efficacious and increased sodium excretion by 26.6- and 17.2-fold, respectively, exceeding that of a matched dose of amiloride (13.6-fold increase). 8-Aminoguanosine and 8-aminoguanine also increased glucose excretion by 12.1- and 12.2-fold, respectively, and decreased potassium excretion by 69.1 and 71.0%, respectively. Long-term radiotelemetry studies demonstrated that oral 8-aminoguanosine and 8-aminoguanine (5 mg/kg/day) suppressed deoxycorticosterone/salt-induced hypertension. These experiments demonstrate that some naturally occurring 8-substitued guanosine and guanine compounds, particularly 8-aminoguanosine and 8-aminoguanine, are potent and efficacious potassium-sparing diuretics/natriuretics that may represent a novel class of antihypertensive diuretics.

Tratamentul cu diuretice în insuficienţa cardiacă cronică

Heart failure is a major public health problem in developed countries. Many of the clinical manifestations of heart failure are due to congestion and fluid retention, therefore diuretic therapy occupied for a long time an important place in the management of these patients. All diuretics increase the excretion of water from the body, each of the classes of diuretics achieving this effect in a distinct manner. Given the magnitude of their effect, loop diuretics are the central pillar of diuretic therapy in many patients with heart failure. Resistance to diuretic therapy is one of the management issues for medical science, which is looking for solutions.

Clinical outcomes according to QRS duration and morphology in the irbesartan in patients with heart failure and preserved systolic function (I-PRESERVE) trial.

The aims of this study were to describe the prevalence of QRS prolongation and abnormal QRS morphology in patients with heart failure and preserved ejection fraction (HF-PEF) and to examine the relationship between these QRS abnormalities and clinical outcomes. We categorized patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-PRESERVE) according to QRS duration <120 vs. ≥120 ms and QRS morphology: normal, left bundle branch block (LBBB), and right bundle branch block (RBBB) or other non-specific intra-ventricular conduction defect (IVCD). The outcomes examined were the composite of cardiovascular death or heart failure hospitalization (and its components) and all-cause mortality. Of the 4128 patients enrolled in I-PRESERVE, 3754 were included in the present analyses. A total of 606 patients had a QRS duration ≥120 ms, 302 had LBBB and 742 had RBBB/IVCD. Patients with an abnormal QRS had evidence of more severe heart failure [lower left ventricular ejection fraction, lower estimated glomerular filtration rate, higher N-terminal pro-B-type natriuretic peptide (NT-proBNP)] and worse clinical status (higher New York Heart Association functional class and greater use of diuretics). Both abnormalities of QRS duration and QRS morphology were associated with worse outcomes. The rates of the composite outcome were: 6.0 and 9.3 per 100 patient years in the <120 ms and ≥120 ms groups, respectively [adjusted hazard ratio (HR) 1.32, 95% confidence interval (CI) 1.11-1.57; P = 0.002) and 6.0, 7.7 and 8.7 per 100 patient years in the normal, non-LBBB and LBBB groups, respectively (adjusted HR 1.19, 95% CI 1.00-1.42, P = 0.046; and HR 1.31, 95% CI 1.03-1.66, P = 0.026, respectively, compared with normal). The heightened risk related to QRS abnormalities persisted after adjustment for other prognostic variables, including NT-proBNP. We found that both prolongation of QRS duration and abnormal QRS morphology were associated with a high risk of fatal and non-fatal adverse outcomes in heart failure with preserved ejection fraction.

Diuretics in the treatment of hypertension.

Diuretics have long been used for the treatment of hypertension. Thiazide diuretics are the most commonly prescribed diuretics for hypertension, but other classes of diuretics may be useful in alternative circumstances. Although diuretics are no longer considered the preferred agent for treatment of hypertension in adults and children, they remain acceptable first-line options. Diuretics effectively decrease blood pressure in hypertensive patients, and in adults with hypertension reduce the risk of adverse cardiovascular outcomes. Because of varied pharmacokinetic and pharmacodynamic differences, chlorthalidone may be the preferred thiazide diuretic in the treatment of primary hypertension. Other types of diuretics (e.g., loop, potassium sparing) may be useful for the treatment of hypertension related to chronic kidney disease (CKD) and other varied conditions. Common side effects of thiazides are mostly dose-related and involve electrolyte and metabolic abnormalities.

Is there a preferred diuretic class for patients with renal impairment and hypertension?

It is widely believed that “high-ceiling” loop diuretics are required in patients with renal impairment and that “low-ceiling” thiazides are not sufficiently potent to cause meaningful natriuresis and diuresis. If this statement is true, at what level of renal function do thiazides lose their punch? Another related issue is the enlightened use of diuretic combinations. Use of diuretics in chronic kidney disease and hypertension has been addressed in the many guidelines, but further insight is provided in this installment of the “Controversies” series by two well-known authorities, William Elliott, M.D. Ph.D. and Rajiv Agarwal, M.D.

Evaluating the extent of pharmaceuticals in surface waters of the United States using a National-scale Rivers and Streams Assessment survey.

To assess the potential exposure of aquatic ecosystems to active pharmaceutical ingredients, the authors conducted a national-scale, probability-based statistical survey of the occurrence of these compounds in surface waters of the United States. The survey included 182 sampling sites and targeted rivers with close proximity to urban areas. The 46 analytes reported represent many classes of active pharmaceutical ingredients (APIs), including antibiotics, diuretics, antihypertensives, anticonvulsants, and antidepressants. Of the 46 analytes, 37 were detected in at least 1 sampling location. Sulfamethoxazole (an antibiotic) was the most frequently detected compound, being measured in 141 of the 182 surface waters surveyed at concentrations ranging up to 570 ng/L. Ten of the compounds were detected in 20% or more of the sampling sites. Weighted means of the analytical measurements are used with the statistical survey design and analysis to provide national estimates of the extent of contamination for these APIs in the nation's urban rivers. Published 2015 Wiley Periodicals, Inc. on behalf of SETAC. This article is a US Government work and as such, is in the public domain in the United States of America.

PP.07.07

Objective: The aim of this study was to characterize the antihypertensive classes most prescribed and the amount of these drugs consumed daily in the pharmacological treatment of hypertension in the public health system. Design and method: This is a descriptive study of a quantitative approach performed in 2014 with 757 people registered in the Family Healthcare Units of a municipality of Minas Gerais and São Paulo from a sample calculated by the Open Epi Version 2 software. The study was approved by the Research Ethics Committee of the Ribeirão Preto School of Nursing of University of São Paulo, CAAE: 02313012.4.0000.5393. For data collection instruments were used to validate and characterize the sample and to survey the antihypertensive medications used. Results: This study showed the predominance of women aged between 50 and 69 years with incomplete primary education and hypertension diagnosis time of more than 10 years. At the time of data collection, 218 (54.9 %) people in the state of Minas Gerais had normal blood pressure and 158 (43.8%) people in the state of São Paulo. It was found that drug treatment occurs predominantly in combination with the class of thiazide diuretics associated with angiotensin II antagonists. The study shows that 253 (63.7 %) people with hypertension enrolled in the Family Healthcare Units consume more than one drug per day in the last week in Minas Gerais and 201 (55.8 %) in São Paulo. Conclusions: The data presented supports the conclusion that the antihypertensive prescriptions for the sample are consistent with the recommended guidelines from the primary care documents of the Ministry of Health, since the antihypertensives consumed by users of the public health system are in a combination recognized as effective.

Blood pressure-lowering efficacy of loop diuretics for primary hypertension.

Antihypertensive drugs from the thiazide diuretic drug class have been shown to reduce mortality and cardiovascular morbidity. Loop diuretics are indicated and used to treat hypertension, but a systematic review of their blood pressure-lowering efficacy or effectiveness in terms of reducing cardiovascular mortality or morbidity from randomized controlled trial (RCT) evidence has not been conducted. To determine the dose-related decrease in systolic or diastolic blood pressure, or both, as well as adverse events leading to participant withdrawal and adverse biochemical effects (serum potassium, uric acid, creatinine, glucose and lipids profile) due to loop diuretics versus placebo control in the treatment of people with primary hypertension. We searched the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, 2014, Issue 9), MEDLINE, MEDLINE In-Process, EMBASE, and ClinicalTrials.gov to 27 October 2014. We included double-blind randomized placebo-controlled trials of at least three weeks duration comparing loop diuretic with a placebo in people with primary hypertension defined as blood pressure greater than 140/90 mmHg at baseline. Two review authors independently assessed the risk of bias and extracted data. We used weighted mean difference and a fixed effects model to combine continuous outcome data. We analysed the drop outs due to adverse effects using relative risk ratio. Nine trials evaluated the dose-related blood pressure-lowering efficacy of five drugs within the loop diuretics class (furosemide 40 mg to 60 mg, cicletanine 100 mg to 150 mg, piretanide 3 mg to 6 mg, indacrinone enantiomer -2.5 mg to -10.0/+80 mg, and etozolin 200 mg) in 460 people with baseline blood pressure of 162/103 mmHg for a mean duration of 8.8 weeks. The best estimate of systolic/diastolic blood pressure-lowering efficacy of loop diuretics was -7.9 (-10.4 to -5.4) mmHg/ -4.4 (-5.9 to -2.8) mmHg. Withdrawals due to adverse effects and serum biochemical changes did not show a significant difference.We performed additional searches in 2012 and 2014, which found no additional trials meeting the minimum inclusion criteria. Based on the limited number of published RCTs, the systolic/diastolic blood pressure-lowering effect of loop diuretics is -8/-4 mmHg, which is likely an overestimate. We graded the quality of evidence for both systolic and diastolic blood pressure estimates as "low" due to the high risk of bias of included studies and the high likelihood of publication bias. We found no clinically meaningful blood pressure-lowering differences between different drugs within the loop diuretic class. The dose-ranging effects of loop diuretics could not be evaluated. The review did not provide a good estimate of the incidence of harms associated with loop diuretics because of the short duration of the trials and the lack of reporting of adverse effects in many of the trials.

Computational and Functional Analyses of a Small-Molecule Binding Site in ROMK

The renal outer medullary potassium channel (ROMK, or Kir1.1, encoded by KCNJ1) critically regulates renal tubule electrolyte and water transport and hence blood volume and pressure. The discovery of loss-of-function mutations in KCNJ1 underlying renal salt and water wasting and lower blood pressure has sparked interest in developing new classes of antihypertensive diuretics targeting ROMK. The recent development of nanomolar-affinity small-molecule inhibitors of ROMK creates opportunities for exploring the chemical and physical basis of ligand-channel interactions required for selective ROMK inhibition. We previously reported that the bis-nitro-phenyl ROMK inhibitor VU591 exhibits voltage-dependent knock-off at hyperpolarizing potentials, suggesting that the binding site is located within the ion-conduction pore. In this study, comparative molecular modeling and in silico ligand docking were used to interrogate the full-length ROMK pore for energetically favorable VU591 binding sites. Cluster analysis of 2498 low-energy poses resulting from 9900 Monte Carlo docking trajectories on each of 10 conformationally distinct ROMK comparative homology models identified two putative binding sites in the transmembrane pore that were subsequently tested for a role in VU591-dependent inhibition using site-directed mutagenesis and patch-clamp electrophysiology. Introduction of mutations into the lower site had no effect on the sensitivity of the channel to VU591. In contrast, mutations of Val168 or Asn171 in the upper site, which are unique to ROMK within the Kir channel family, led to a dramatic reduction in VU591 sensitivity. This study highlights the utility of computational modeling for defining ligand-ROMK interactions and proposes a mechanism for inhibition of ROMK.

Analysis of usage of diuretics in Medical intensive care unit of SIMS-Shimoga a tertiary care hospital.

Background: Patients are admitted in the intensive care unit (ICU) with a history of various acute and chronic clinical conditions associated with organ failures. Compared to the patients admitted in the general wards the mortality and morbidity are high in ICU patients. The patients in ICU are subjected to multiple drugs; diuretic agents are liberally and deliberately used in this setup despite the lack of evidence supporting their benefits. Methods: The main aim of the study was to know the extent of use of diuretics in the ICU set up, to categorize the use of diuretics in different clinical conditions and different classes of diuretics used. The study also tried to determine adverse events and outcome in critically ill patients. The study was a retrospective cross-sectional of 3 months duration conducted in all patients admitted in the medical ICU of the tertiary care center. The study mainly concentrated on the usage of diuretics and related aspects. Results: Loop diuretics (54.81%) composed the major class, thiazides (30.84%). Potassium sparing diuretics (7%) and osmotic diuretics (7%) and carbonic anhydrase inhibitors (1%) were the other class of diuretics. The classes of drugs used in ICU along with diuretics were antibiotics (30%), analgesics (9.5%), anti-inflammatory (6.36%), and drugs acting on blood (10.18%) of total drugs used in ICU. Antacids/laxatives (7.3%) and antiemetic (4.8%), the rest of drugs (15%) of drugs used in ICU. Conclusion: In almost 95% of cases, the combination of other drugs along with diuretics was considered to be rational.