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Naunyn-Schmiedeberg's Archives of... Jun 2022Diuretics are drugs that increase the flow of urine. They are commonly used to treat edema, hypertension, and heart failure. Typically, the pharmacological group... (Review)
Review
Diuretics are drugs that increase the flow of urine. They are commonly used to treat edema, hypertension, and heart failure. Typically, the pharmacological group consists of five classes: thiazide diuretics, loop diuretics, potassium-sparing diuretics, osmotic diuretics, and carbonic anhydrase inhibitors. This traditional classification and the nomenclature of diuretics have not changed over the last decades, which means that it was not adapted to current pharmacological research. Modern approaches in the field of pharmacological nomenclature suggest the introduction of mechanism-based drug class designations, which is not yet reflected in the group of diuretics. Moreover, included drug classes have lost their relevance as diuretic agents. Carbonic anhydrase inhibitors, for example, are mainly used in the treatment of glaucoma. Newer agents such as vasopressin-2 receptor antagonists or SGLT2 inhibitors possess diuretic properties but are not included in the pharmacological group. This review discusses the currentness of the pharmacological classification of diuretics. We elaborate changes in the field of nomenclature, the contemporary medical use of classical diuretics, and new diuretic agents.
Topics: Carbonic Anhydrase Inhibitors; Diuretics; Heart Failure; Humans; Hypertension; Sodium Chloride Symporter Inhibitors
PubMed: 35294605
DOI: 10.1007/s00210-022-02228-0 -
Journal of Clinical Hypertension... Sep 2011KEY POINTS AND PRACTICAL RECOMMENDATIONS: • Although chlorthalidone and hydrochlorothiazide are structurally similar, they are very different pharmacokinetically,... (Review)
Review
KEY POINTS AND PRACTICAL RECOMMENDATIONS: • Although chlorthalidone and hydrochlorothiazide are structurally similar, they are very different pharmacokinetically, with chlorthalidone having both an extremely long half-life (approximately 40 to 60 hours) and a large volume of distribution, with gradual elimination from the plasma compartment by tubular secretion. • Furosemide usage, the most widely used diuretic in the loop diuretic class, can be complicated by extremely erratic absorption, with a bioavailability range of 12% to 112%. • Chlorthalidone, at a dose of 25 mg, is comparatively more potent than 50 mg of hydrochlorothiazide, particularly as related to overnight blood pressure reduction. • In ALLHAT, there was no difference among chlorthalidone, amlodipine, lisinopril, and doxazosin for the primary outcome or mortality. • Secondary outcomes were similar except for a 38% higher rate of heart failure with amlodipine; a 10% higher rate of combined cardiovascular disease, a 15% higher rate of stroke, and a 19% higher rate of heart failure with lisinopril; and a 20% higher rate of cardiovascular disease, a 20% higher rate of stroke (40% higher rate in blacks), and an 80% higher rate of heart failure with doxazosin, compared with chlorthalidone. • The ACCOMPLISH study may affect future practice guidelines as a result of its findings favoring the amlodipine/benazepril combination; however, the generalizability to patient populations with a lesser cardiovascular risk profile remains in question and the dose of hydrochlorothiazide was only 12.5 mg to 25 mg daily, which was a dose lower than that used in placebo-controlled trials using hydrochlorothiazide. • Certain low-renin patient groups (eg, blacks, the elderly, and diabetics) as well as those who manifest the metabolic syndrome are commonly more responsive to thiazide-type diuretic therapy. • Diuretics can be successfully combined with β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, centrally acting agents, and even calcium channel blockers. • Although thiazide-type diuretics are among the best-tolerated antihypertensive agents in terms of symptomatic adverse effects, diuretic-related adverse side effects include those with established mechanisms (eg, such as electrolyte changes and/or metabolic abnormalities) and other side effects, which are less well understood mechanistically (eg, impotence), although the latter is not universally accepted as a diuretic-related side effect. • Thiazide-induced hypokalemia is associated with increased blood glucose, and treatment of thiazide-induced hypokalemia may reverse glucose intolerance and possibly prevent diabetes. • Thiazide-induced hyperuricemia occurs as a result of volume contraction and competition with uric acid for renal tubular secretion, but does not necessarily contraindicate using a thiazide, especially if a uric acid-lowering drug such as allopurinol is being used. • Adverse interactions include the blunting of thiazide effects by nonsteroidal anti-inflammatory drugs and the potential to increase fatigue, lethargy, and increase in glucose when combined with β-blockers. • Thiazide-type diuretics are useful first-line agents in the treatment of hypertension because they have been proven to reduce cardiovascular mortality and morbidity in systolic and diastolic forms of hypertension and do so at low cost. • Loop diuretics should not be used as first-line therapy in hypertension since there are no outcome data with them. They should be reserved for conditions of clinically significant fluid overload (eg, heart failure and significant fluid retention with vasodilator drugs, such as minoxidil) or with advanced renal failure and can be combined with thiazide-type diuretics.
Topics: Antihypertensive Agents; Humans; Hypertension; Hyperuricemia; Hypokalemia; Risk Management; Sodium Chloride Symporter Inhibitors; Sodium Potassium Chloride Symporter Inhibitors; Treatment Outcome
PubMed: 21896142
DOI: 10.1111/j.1751-7176.2011.00512.x -
Circulation Research Mar 2019Resistant hypertension (RHTN) is defined as uncontrolled blood pressure despite the use of ≥3 antihypertensive agents of different classes, including a diuretic,... (Review)
Review
Resistant hypertension (RHTN) is defined as uncontrolled blood pressure despite the use of ≥3 antihypertensive agents of different classes, including a diuretic, usually thiazide-like, a long-acting calcium channel blocker, and a blocker of the renin- angiotensin system, either an ACE (angiotensin-converting enzyme) inhibitor or an ARB (angiotensin receptor blocker), at maximal or maximally tolerated doses. Antihypertensive medication nonadherence and the white coat effect, defined as elevated blood pressure when measured in clinic but controlled when measured outside of clinic, must be excluded to make the diagnosis. RHTN is a high-risk phenotype, leading to increased all-cause mortality and cardiovascular disease outcomes. Healthy lifestyle habits are associated with reduced cardiovascular risk in patients with RHTN. Aldosterone excess is common in patients with RHTN, and addition of spironolactone or amiloride to the standard 3-drug antihypertensive regimen is effective at getting the blood pressure to goal in most of these patients. Refractory hypertension is defined as uncontrolled blood pressure despite use of ≥5 antihypertensive agents of different classes, including a long-acting thiazide-like diuretic and an MR (mineralocorticoid receptor) antagonist, at maximal or maximally tolerated doses. Fluid retention, mediated largely by aldosterone excess, is the predominant mechanism underlying RHTN, while patients with refractory hypertension typically exhibit increased sympathetic nervous system activity.
Topics: Aldosterone; Animals; Antihypertensive Agents; Blood Pressure; Drug Resistance; Drug Therapy, Combination; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Risk Factors; Sodium Chloride Symporter Inhibitors; Sympathetic Nervous System; Sympatholytics; Treatment Outcome; Water-Electrolyte Balance
PubMed: 30920924
DOI: 10.1161/CIRCRESAHA.118.312156 -
The New England Journal of Medicine Mar 2023Nephrolithiasis is one of the most common conditions affecting the kidney and is characterized by a high risk of recurrence. Thiazide diuretic agents are widely used for... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Nephrolithiasis is one of the most common conditions affecting the kidney and is characterized by a high risk of recurrence. Thiazide diuretic agents are widely used for prevention of the recurrence of kidney stones, but data regarding the efficacy of such agents as compared with placebo are limited. Furthermore, dose-response data are also limited.
METHODS
In this double-blind trial, we randomly assigned patients with recurrent calcium-containing kidney stones to receive hydrochlorothiazide at a dose of 12.5 mg, 25 mg, or 50 mg once daily or placebo once daily. The main objective was to investigate the dose-response effect for the primary end point, a composite of symptomatic or radiologic recurrence of kidney stones. Radiologic recurrence was defined as the appearance of new stones on imaging or the enlargement of preexisting stones that had been observed on the baseline image. Safety was also assessed.
RESULTS
In all, 416 patients underwent randomization and were followed for a median of 2.9 years. A primary end-point event occurred in 60 of 102 patients (59%) in the placebo group, in 62 of 105 patients (59%) in the 12.5-mg hydrochlorothiazide group (rate ratio vs. placebo, 1.33; 95% confidence interval [CI], 0.92 to 1.93), in 61 of 108 patients (56%) in the 25-mg group (rate ratio, 1.24; 95% CI, 0.86 to 1.79), and in 49 of 101 patients (49%) in the 50-mg group (rate ratio, 0.92; 95% CI, 0.63 to 1.36). There was no relation between the hydrochlorothiazide dose and the occurrence of a primary end-point event (P = 0.66). Hypokalemia, gout, new-onset diabetes mellitus, skin allergy, and a plasma creatinine level exceeding 150% of the baseline level were more common among patients who received hydrochlorothiazide than among those who received placebo.
CONCLUSIONS
Among patients with recurrent kidney stones, the incidence of recurrence did not appear to differ substantially among patients receiving hydrochlorothiazide once daily at a dose of 12.5 mg, 25 mg, or 50 mg or placebo once daily. (Funded by the Swiss National Science Foundation and Inselspital; NOSTONE ClinicalTrials.gov number, NCT03057431.).
Topics: Humans; Hydrochlorothiazide; Kidney; Kidney Calculi; Sodium Chloride Symporter Inhibitors; Recurrence; Double-Blind Method; Dose-Response Relationship, Drug; Diuretics
PubMed: 36856614
DOI: 10.1056/NEJMoa2209275 -
Clinical Journal of the American... May 2019CKD is common and frequently complicated with hypertension both predialysis and in ESKD. As a major modifiable risk factor for cardiovascular disease in this high-risk... (Review)
Review
CKD is common and frequently complicated with hypertension both predialysis and in ESKD. As a major modifiable risk factor for cardiovascular disease in this high-risk population, treatment of hypertension in CKD is important. We review the mechanisms and indications for the major classes of antihypertensive drugs, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, -adrenergic blocking agents, dihydropyridine calcium channel blockers, thiazide diuretics, loop diuretics, mineralocorticoid receptor blockers, direct vasodilators, and centrally acting -agonists. Recent evidence suggests that -adrenergic blocking agents may have a greater role in patients on dialysis and that thiazide diuretics may have a greater role in patients with advanced CKD. We conclude with sharing our general prescribing algorithm for both patients with predialysis CKD and patients with ESKD on dialysis.
Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Humans; Hypertension; Renal Insufficiency, Chronic; Sodium Chloride Symporter Inhibitors; Vasodilator Agents
PubMed: 30425103
DOI: 10.2215/CJN.04330418 -
Clinical Interventions in Aging 2017Decreased serum sodium concentration is a rather frequent electrolyte disorder in the elderly population because of the presence of factors contributing to increased... (Review)
Review
Decreased serum sodium concentration is a rather frequent electrolyte disorder in the elderly population because of the presence of factors contributing to increased antidiuretic hormone, the frequent prescription of drugs associated with hyponatremia and also because of other mechanisms such as the "tea and toast" syndrome. The aim of this review is to present certain challenges in the evaluation and treatment of hyponatremia in the elderly population and provide practical solutions. Hyponatremia in elderly subjects is mainly caused by drugs (more frequently thiazides and antidepressants), the syndrome of inappropriate antidiuretic hormone secretion (SIAD) or endocrinopathies; however, hyponatremia is multifactorial in a significant proportion of patients. Special attention is needed in the elderly population to exclude endocrinopathies as a cause of hyponatremia before establishing the diagnosis of SIAD, which then requires a stepped diagnostic approach to reveal its underlying cause. The treatment of hyponatremia depends on the type of hyponatremia. Special attention is also needed to correct serum sodium levels at the appropriate rate, especially in chronic hyponatremia, in order to avoid the osmotic demyelination syndrome. In conclusion, both the evaluation and the treatment of hyponatremia pose many challenges in the elderly population.
Topics: Aged; Antidepressive Agents; Humans; Hyponatremia; Hypopituitarism; Inappropriate ADH Syndrome; Sodium Chloride Symporter Inhibitors
PubMed: 29180859
DOI: 10.2147/CIA.S138535 -
Journal of the American College of... Nov 2010Volume overload is an important clinical target in heart failure management, typically addressed using loop diuretics. An important and challenging subset of heart... (Review)
Review
Volume overload is an important clinical target in heart failure management, typically addressed using loop diuretics. An important and challenging subset of heart failure patients exhibit fluid overload despite significant doses of loop diuretics. One approach to overcome loop diuretic resistance is the addition of a thiazide-type diuretic to produce diuretic synergy via "sequential nephron blockade," first described more than 40 years ago. Although potentially able to induce diuresis in patients otherwise resistant to high doses of loop diuretics, this strategy has not been subjected to large-scale clinical trials to establish safety and clinical efficacy. We summarize the existing literature evaluating the combination of loop and thiazide diuretics in patients with heart failure in order to describe the possible benefits and hazards associated with this therapy. Combination diuretic therapy using any of several thiazide-type diuretics can more than double daily urine sodium excretion to induce weight loss and edema resolution, at the risk of inducing severe hypokalemia in addition to hyponatremia, hypotension, and worsening renal function. We provide considerations about prudent use of this therapy and review potential misconceptions about this long-used diuretic approach. Finally, we seek to highlight the need for pragmatic clinical trials for this commonly used therapy.
Topics: Animals; Diuretics; Drug Resistance; Drug Therapy, Combination; Heart Failure; Humans; Kidney; Randomized Controlled Trials as Topic; Sodium Chloride Symporter Inhibitors; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 21029871
DOI: 10.1016/j.jacc.2010.06.034 -
Nature Feb 2023The sodium-chloride cotransporter (NCC) is critical for kidney physiology. The NCC has a major role in salt reabsorption in the distal convoluted tubule of the nephron,...
The sodium-chloride cotransporter (NCC) is critical for kidney physiology. The NCC has a major role in salt reabsorption in the distal convoluted tubule of the nephron, and mutations in the NCC cause the salt-wasting disease Gitelman syndrome. As a key player in salt handling, the NCC regulates blood pressure and is the target of thiazide diuretics, which have been widely prescribed as first-line medications to treat hypertension for more than 60 years. Here we determined the structures of human NCC alone and in complex with a commonly used thiazide diuretic using cryo-electron microscopy. These structures, together with functional studies, reveal major conformational states of the NCC and an intriguing regulatory mechanism. They also illuminate how thiazide diuretics specifically interact with the NCC and inhibit its transport function. Our results provide critical insights for understanding the Na-Cl cotransport mechanism of the NCC, and they establish a framework for future drug design and for interpreting disease-related mutations.
Topics: Humans; Cryoelectron Microscopy; Diuretics; Drug Design; Gitelman Syndrome; Sodium Chloride Symporter Inhibitors; Thiazides
PubMed: 36792826
DOI: 10.1038/s41586-023-05718-0 -
British Journal of Clinical Pharmacology Mar 2022Diverse genetic and/or external factors may induce psoriasis. Drug exposure is 1 such prominent external factor; antihypertensive drugs are reportedly associated with... (Meta-Analysis)
Meta-Analysis Review
AIMS
Diverse genetic and/or external factors may induce psoriasis. Drug exposure is 1 such prominent external factor; antihypertensive drugs are reportedly associated with psoriasis, but study results have been inconsistent. In this context, we investigated the associations between antihypertensive drugs and incidence if psoriasis via a systematic literature review and meta-analysis.
METHODS
Literature search in databases such as PubMed, Embase and Web of Science was conducted on 8 January 2021, and obtained data were pooled for meta- and network meta-analysis. Fixed- or random effect models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for evaluating the strength of the associations between antihypertensive drugs and psoriasis incidence. In addition to meta-analysis, Bayesian network meta-analysis was performed. ResultsThirteen eligible studies were included for meta-analysis with 6 378 116 individuals and 8 studies for network meta-analysis with 5 615 918 individuals. All antihypertensive drugs were significantly associated with psoriasis incidence. In a meta-analysis, the pooled ORs were 1.67 (95% CI: 1.31-2.13) for angiotensin-converting enzyme (ACE) inhibitors, 1.40 (95% CI: 1.20-1.63) for β-blockers, 1.53 (95% CI: 1.23-1.89) for calcium-channel blockers (CCBs), and 1.70 (95% CI: 1.40-2.06) for thiazide diuretics. For the comparative risks of psoriasis among antihypertensive drugs in the network meta-analysis, ORs were 2.09 (95% CI: 1.39-3.18) for ACE inhibitors, 1.35 (95% CI: 0.99-1.91) for BBs, 1.53 (95% CI: 1.07-2.24) for CCBs and 1.80 (95% CI: 1.23-2.66) for thiazide diuretics.
CONCLUSION
This study confirmed the associations between antihypertensive drugs and psoriasis; ACE inhibitors, BBs, CCBs and thiazide diuretics increased the risk of psoriasis. Therefore, antihypertensive drug users should be carefully monitored for psoriasis.
Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Bayes Theorem; Calcium Channel Blockers; Humans; Hypertension; Network Meta-Analysis; Psoriasis; Sodium Chloride Symporter Inhibitors
PubMed: 34611920
DOI: 10.1111/bcp.15060 -
The Cochrane Database of Systematic... Apr 2018This is the first update of a review published in 2009. Sustained moderate to severe elevations in resting blood pressure leads to a critically important clinical... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is the first update of a review published in 2009. Sustained moderate to severe elevations in resting blood pressure leads to a critically important clinical question: What class of drug to use first-line? This review attempted to answer that question.
OBJECTIVES
To quantify the mortality and morbidity effects from different first-line antihypertensive drug classes: thiazides (low-dose and high-dose), beta-blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers (ARB), and alpha-blockers, compared to placebo or no treatment.Secondary objectives: when different antihypertensive drug classes are used as the first-line drug, to quantify the blood pressure lowering effect and the rate of withdrawal due to adverse drug effects, compared to placebo or no treatment.
SEARCH METHODS
The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to November 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We contacted authors of relevant papers regarding further published and unpublished work.
SELECTION CRITERIA
Randomized trials (RCT) of at least one year duration, comparing one of six major drug classes with a placebo or no treatment, in adult patients with blood pressure over 140/90 mmHg at baseline. The majority (over 70%) of the patients in the treatment group were taking the drug class of interest after one year. We included trials with both hypertensive and normotensive patients in this review if the majority (over 70%) of patients had elevated blood pressure, or the trial separately reported outcome data on patients with elevated blood pressure.
DATA COLLECTION AND ANALYSIS
The outcomes assessed were mortality, stroke, coronary heart disease (CHD), total cardiovascular events (CVS), decrease in systolic and diastolic blood pressure, and withdrawals due to adverse drug effects. We used a fixed-effect model to to combine dichotomous outcomes across trials and calculate risk ratio (RR) with 95% confidence interval (CI). We presented blood pressure data as mean difference (MD) with 99% CI.
MAIN RESULTS
The 2017 updated search failed to identify any new trials. The original review identified 24 trials with 28 active treatment arms, including 58,040 patients. We found no RCTs for ARBs or alpha-blockers. These results are mostly applicable to adult patients with moderate to severe primary hypertension. The mean age of participants was 56 years, and mean duration of follow-up was three to five years.High-quality evidence showed that first-line low-dose thiazides reduced mortality (11.0% with control versus 9.8% with treatment; RR 0.89, 95% CI 0.82 to 0.97); total CVS (12.9% with control versus 9.0% with treatment; RR 0.70, 95% CI 0.64 to 0.76), stroke (6.2% with control versus 4.2% with treatment; RR 0.68, 95% CI 0.60 to 0.77), and coronary heart disease (3.9% with control versus 2.8% with treatment; RR 0.72, 95% CI 0.61 to 0.84).Low- to moderate-quality evidence showed that first-line high-dose thiazides reduced stroke (1.9% with control versus 0.9% with treatment; RR 0.47, 95% CI 0.37 to 0.61) and total CVS (5.1% with control versus 3.7% with treatment; RR 0.72, 95% CI 0.63 to 0.82), but did not reduce mortality (3.1% with control versus 2.8% with treatment; RR 0.90, 95% CI 0.76 to 1.05), or coronary heart disease (2.7% with control versus 2.7% with treatment; RR 1.01, 95% CI 0.85 to 1.20).Low- to moderate-quality evidence showed that first-line beta-blockers did not reduce mortality (6.2% with control versus 6.0% with treatment; RR 0.96, 95% CI 0.86 to 1.07) or coronary heart disease (4.4% with control versus 3.9% with treatment; RR 0.90, 95% CI 0.78 to 1.03), but reduced stroke (3.4% with control versus 2.8% with treatment; RR 0.83, 95% CI 0.72 to 0.97) and total CVS (7.6% with control versus 6.8% with treatment; RR 0.89, 95% CI 0.81 to 0.98).Low- to moderate-quality evidence showed that first-line ACE inhibitors reduced mortality (13.6% with control versus 11.3% with treatment; RR 0.83, 95% CI 0.72 to 0.95), stroke (6.0% with control versus 3.9% with treatment; RR 0.65, 95% CI 0.52 to 0.82), coronary heart disease (13.5% with control versus 11.0% with treatment; RR 0.81, 95% CI 0.70 to 0.94), and total CVS (20.1% with control versus 15.3% with treatment; RR 0.76, 95% CI 0.67 to 0.85).Low-quality evidence showed that first-line calcium channel blockers reduced stroke (3.4% with control versus 1.9% with treatment; RR 0.58, 95% CI 0.41 to 0.84) and total CVS (8.0% with control versus 5.7% with treatment; RR 0.71, 95% CI 0.57 to 0.87), but not coronary heart disease (3.1% with control versus 2.4% with treatment; RR 0.77, 95% CI 0.55 to 1.09), or mortality (6.0% with control versus 5.1% with treatment; RR 0.86, 95% CI 0.68 to 1.09).There was low-quality evidence that withdrawals due to adverse effects were increased with first-line low-dose thiazides (5.0% with control versus 11.3% with treatment; RR 2.38, 95% CI 2.06 to 2.75), high-dose thiazides (2.2% with control versus 9.8% with treatment; RR 4.48, 95% CI 3.83 to 5.24), and beta-blockers (3.1% with control versus 14.4% with treatment; RR 4.59, 95% CI 4.11 to 5.13). No data for these outcomes were available for first-line ACE inhibitors or calcium channel blockers. The blood pressure data were not used to assess the effect of the different classes of drugs as the data were heterogeneous, and the number of drugs used in the trials differed.
AUTHORS' CONCLUSIONS
First-line low-dose thiazides reduced all morbidity and mortality outcomes in adult patients with moderate to severe primary hypertension. First-line ACE inhibitors and calcium channel blockers may be similarly effective, but the evidence was of lower quality. First-line high-dose thiazides and first-line beta-blockers were inferior to first-line low-dose thiazides.
Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Coronary Disease; Humans; Hypertension; Middle Aged; Randomized Controlled Trials as Topic; Sodium Chloride Symporter Inhibitors; Stroke; Thiazides
PubMed: 29667175
DOI: 10.1002/14651858.CD001841.pub3