Effects of Hydroflumethiazide in Congestive Heart Failure: Renal Electrolyte Excretion Related to Urinary Thiazide Excretion and Aldosterone

Abstract: The effect of hydroflumethiazide (HFT) on renal excretion of sodium, chloride, and potassium was studied in congestive heart failure and related to urinary excretion of thiazide and aldosterone. HFT 75 or 150 mg was administered orally once daily for 4 days to 8 male patients with roentgenological evidence of enlarged heart and slight or no peripheral oedema receiving digitalis and controlled diet. Urinary excretion of HFT did not change after repeated doses, whereas urinary excretion of a metabolite increased significantly. Initially, HFT induced a significant increase in the urinary excretion of sodium and potassium. After repeated doses, the natriuretic effect declined gradually in 6 of the patients. There was consistently a small natriuretic effect and a large kaliuretic effect at high serum aldosterone concentrations and high urine aldosterone excretion rates, whereas at low aldosterone levels, there was a wide range in magnitude of these effects. Relationships of the log urinary excretion rate of HFT to the increase in urinary excretion rate of sodium, chloride, and potassium showed positive and significant correlations. It was concluded that reduced natriuretic effect of HFT in congestive heart failure is not due to reduced delivery of thiazide to renal tubular cells but to compensatory adjustments of the kidney in part induced by aldosterone.     

A Systematic Review and Meta-Analysis of Metolazone Compared to Chlorothiazide for Treatment of Acute Decompensated Heart Failure

Treatment of volume overload in the setting of acute decompensated heart failure (ADHF) is typically achieved through the use of loop diuretics. While they are highly effective, some patients may develop loop diuretic resistance. One strategy to overcome this scenario includes sequential nephron blockade with a thiazide-type diuretic; however, it is unknown which thiazide-type diuretic used in this setting is most effective. A systematic review and meta-analysis were performed to compare the efficacy and safety of chlorothiazide with metolazone as add-on therapy in the setting of loop diuretic resistance for the treatment of ADHF. Literature searches were conducted through PubMed, Google Scholar, and Science Direct from inception through February 2020 using the following search terms alone or in combination: metolazone, chlorothiazide, acute decompensated heart failure, loop diuretic, and urine output. All English-language prospective and retrospective trials and abstracts comparing metolazone to chlorothiazide for the treatment of ADHF were evaluated. Studies were included if they analyzed urine output for at least 24 hours in patients with ADHF. Meta-analysis was conducted to evaluate pooled effect size by using a random-effect model. Primary outcomes included net and total urine output. Secondary outcomes included commonly reported safety outcomes. Four studies comparing the use of metolazone to chlorothiazide as an adjunct to loop diuretics to treat ADHF were included in the evaluation. Metolazone was as effective as chlorothiazide to augment loop diuretic therapy in ADHF in most studies with no pooled difference in net or total urine output. However, there were notable differences in baseline loop diuretic dosing, ejection fraction, renal function, race, and endpoint timing across studies. Adverse effects were commonly observed and included electrolyte abnormalities, change in renal function, and hypotension but were comparable between groups. Metolazone is as effective as chlorothiazide as add-on to loop diuretics in treating ADHF without an increase in safety concerns.     

Reversal of an unfavorable effect of hydrochlorothiazide compared to angiotensin converting enzyme inhibitor on serum uric acid and oxypurine levels by estrogen–progestin therapy in hypertensive postmenopausal women

Background: The aim was to assess the effect of estrogen–progestin therapy (EPT) on serum levels of uric acid (SUA) and its precursors xanthine (X) and hypoxanthine (HX), and on uric acid (UA) renal excretion in hypertensive postmenopausal women treated with an angiotensin-converting enzyme inhibitor (ACEI) or thiazide diuretic (HCTZ) (ClinicalTrials.gov identifier: NCT03921736, registered 19 April 2019).

Methods: Postmenopausal women with untreated essential hypertension were recruited to the study. The control group consisted of 40 postmenopausal women with normal blood pressure. Hypertensive women were randomized to two groups: hydrochlorothiazide (n?=?50) or perindopril (n?=?50) and to a group receiving or not receiving EPT (EPT+/EPT?) due to vasomotor symptoms. The follow-up period was one year. Blood pressure measurements as well as blood tests for SUA and its precursors X and HX were performed at baseline and after 12?months.

Results: In hypertensive women, baseline serum X and HX were significantly higher when compared to the group of normotensive women. Treatment with HCTZ led to a statistically significant increase in SUA in the subgroup of EPT- women. In this group concentrations of X and HX increased significantly after 12?months. UA/X significantly decreased after treatment with HCTZ. Lack of EPT resulted in a decrease of renal plasma flow in the HCTZ group. However, in the HCTZ and EPT?+?group, SUA decreased significantly when compared to baseline. None of these unfavorable effects was observed in the ACEI group regardless of EPT.

Conclusions: 1) EPT prevents the development of hyperuricemia during antihypertensive treatment with thiazide diuretics. 2) Arterial hypertension and menopause cause impairment of UA excretion and increase the levels of SUA and its precursors X and HX. 3) EPT reduces the risk of hyperuricemia in postmenopausal women.     

The sodium/proton exchanger NHA2 regulates blood pressure through a WNK4-NCC dependent pathway in the kidney

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复方缬沙坦与血脂康联合治疗原发性高血压的临床研究

目的评价复方缬沙坦(缬沙坦80mg/氢氯噻嗪12.5mg)联合血脂康(600mg)治疗轻、中度原发性高血压患者的疗效和安全性。方法采用随机、双盲对照研究。将280例轻、中度高血压患者随机分为缬沙坦组和对照组。缬沙坦组患者给予复方缬沙坦(缬沙坦80mg/氢氯噻嗪12.5mg,1次/d)和血脂康(600mg,2次/d)治疗,对照组患者降压药物单用缬沙坦(80mg,1次/d)。治疗中每周测量血压。在治疗8周和结束时评价药物安全性和有效性。结果对于轻、中度原发性高血压患者,缬沙坦组较对照组血压进一步下降,达标率显著高于对照组。治疗结束时平均坐位收缩压均降低5mmHg,平均坐位舒张压多下降3mmHg,缬沙坦组和对照组患者中,血压控制<140/90mmHg者分别占54.1%和40.7%。结论轻、中度原发性高血压患者采用复方缬沙坦联合血脂康治疗,降压效果和达标率均优于单用缬沙坦。     

Fracture risk after thiazide-associated hyponatraemia

Background/Aim: Although thiazide‐type diuretics can promote a positive calcium balance, thiazide can be associated with hyponatraemia, which is recently linked with heightened fracture risk. We examine the chance of developing fracture in patients with and without hyponatraemia after taking thiazide diuretics. Methods: In this single‐centre retrospective study, we followed up a previously published cohort of patients with (n= 223) and without (n= 216) thiazide‐induced hyponatraemia. Results: A total of 61 osteoporotic fractures was recorded during a mean follow‐up period of 82 months. Using univariate regression analysis, the hazard ratio of thiazide‐induced hyponatraemia was 1.78 (95% confidence interval (CI), 1.05–3.03; P= 0.033). Cox proportional hazards regression analysis, however, showed that age, body mass index and diabetes mellitus were the only independent predictors of osteoporotic fractures. No association of a history of thiazide‐induced hyponatraemia and risk of fracture was evident in the final model. Conclusion: Since a history of thiazide‐induced hyponatraemia is associated with osteoporotic fracture in univariate but not multivariate analyses, an alternative explanation is that confounding factors of older age and low body mass index accounted for the apparently increased risk of osteoporotic fracture in patients with thiazide‐induced hyponatraemia.     

Sequential Drug-Induced Severe Hyponatremia in a Minimally Symptomatic, 81-Year-Old Patient

BackgroundThere have been previous cases of medication-induced hyponatremia with various causative agents reported. Severe hyponatremia, a common medical emergency, can vary widely in its presentation, ranging from seizures and comas to no clinical manifestations.Case ReportAn 81-year-old female patient presented to the Emergency Department with history of a fall. She had a known case of hypertension and was recently started on hydrochlorothiazide. When evaluated at the hospital, her sodium level was measured as 106 mmol/L and her clinical symptoms were unremarkable. She was simultaneously diagnosed with a urinary tract infection, for which she was treated with intravenous ciprofloxacin. A few hours after administration, her sodium level fell even further, and she quickly developed symptoms of hyponatremia. After discontinuation of ciprofloxacin and treatment with hypertonic saline (3% NS), she improved and made a full recovery.Why Should an Emergency Physician Be Aware of This?We present an unusual case of minimally symptomatic, severe consecutive multi-medication-induced hyponatremia. As hyponatremia can present asymptomatically, routinely checking sodium levels is recommended, especially when caring for patients who recently experienced a fall or started a thiazide diuretic.     

Post-Obstructive Urinary Concentrating Defect A Case Study in the Role of Prostaglandins

ABSTRACT. A child with post-obstructive urinary concentrating defect was studied for the possible pathophysiological role of prostaglandins and an eventual therapeutic approach. Increased urinary excretion of prostaglandins was corrected by indomethacin, with resultant increased nephrogenous cyclic AMP and partial improvement in the concentrating defect. The addition of a thiazide restored urinary concentration. These results add clinical support to the conception of the important role of prostaglandins in the mechanism of post-obstructive hyposthenuria. This therapeutic regimen is advocated for prolonged post-obstructive concentrating defect.