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Diuretics and their side effects. Dilemma in the treatment of hypertension.

Diuretics have traditionally been the keystone of antihypertensive therapy. A variety of clinical trials, designed to examine the benefit of blood pressure reduction in decreasing morbidity and mortality from hypertension-related cardiovascular disease, have surprisingly failed to show a decrease in coronary artery disease death rate, although other forms of vascular disease were impressively reduced. These trials have consistently used diuretics as the initial therapeutic choice. Such observations have stimulated a reevaluation of the "stepped-care" approach and a critical appraisal of diuretic effects. This review examines the efficacy of diuretics in reducing blood pressure and attempts to identify individuals most likely to respond to these agents. The side effects of diuretic therapy are reviewed in hemodynamic, cardiac, metabolic, and symptomatic terms, but because some of these aspects of diuretic or antihypertensive therapy are detailed elsewhere in this monograph, the present discussion focuses on cardiac, metabolic, hemodynamic, and symptomatic effects. Finally, alternative therapeutic options and guidelines for therapy are outlined.

Arrhythmias, Cardiac↗

Risks of diuretic usage following stroke.

OBJECTIVE: To assess the effects of diuretic use on hydration status following stroke. METHODS: Admission serum hydration markers and neurologic assessments were prospectively recorded for 296 stroke rehabilitation inpatients with stable renal function. Dysphagia was defined by bedside dysphagia evaluation and subsequent modified barium swallow, if necessary. Serum hydration markers were checked at approximate 10-day intervals. Analysis of variance was used to test the effects of clinical variables on serum markers for hydration during the rehabilitation hospital stay. Odds ratios were used to quantify the risks of developing a blood urea nitrogen value > or = 45 mg/dl. RESULTS: The mean peak blood urea nitrogen associated with each of the following were diuretic usage yes/no (33 mg/dl +/- 18/26 +/- 17, P < 0.01), dysphagia yes/no (32 +/- 21/25 +/- 14, P < 0.001), and need for thin-liquid restriction yes/no (34 +/- 20/25 +/- 15, P < 0.001). The odds ratio for developing a peak blood urea nitrogen > or = 45 for patients taking a diuretic with evidence of penetration or aspiration documented by modified barium swallow was (19.8, P < 0.001). The odds ratio for developing a peak blood urea nitrogen > or = 45 for those taking a diuretic who needed thin-liquid restriction was (4.8, P = 0.004). CONCLUSIONS: Diuretic usage was associated with a significant increase in peak blood urea nitrogen across the entire stroke study sample. The highest odds ratio for developing a peak blood urea nitrogen > or = 45 was 19.8 for patients taking a diuretic who had dysphagia plus modified barium swallow evidence of penetration-aspiration.

Aged↗

Diuretic treatment in essential hypertension.

In North America, diuretics remain the most common first-line drug therapy for essential hypertension based on efficacy, safety and cost. The promotion of step-care programmes has firmly established their dominant use on this continent whereas in Europe, particularly in Scandinavia and Great Britain, beta-adrenoceptor blocking agents are more frequently chosen as first-line therapy. On both continents, combined therapy with a diuretic and a beta-blocker is probably the most common second step for patients with blood pressures uncontrolled on a single agent alone and diuretics remain useful, if not essential, to prevent sodium retention commonly observed with other antihypertensive agents. Although the forced loss of sodium and water may be responsible for their initial antihypertensive effect, the mechanism underlying their long-term effect is unknown but probably involves some alteration of vascular smooth muscle reactivity. More recently, concern has been expressed about their long-term safety as larger populations are being exposed to diuretic agents for a significant proportion of their life-span. These concerns include haemodynamic and biochemical consequences of diuretic therapy - excessive tachycardia at rest and with minimal exercise, postural hypotension, hypokalaemia and arrhythmias, muscle cramps or fatigue, glucose intolerance, hyperuricaemia and altered circulating lipids as markers or promotors of atherosclerosis and its complications. At present, there is insufficient evidence to alter the present recommendation of diuretic agents as first-line drug therapy in the treatment of hypertension.

Aged↗

Treating the older hypertensive: beta-blocker or diuretic?

Twenty-six ambulant elderly patients (age range 62 to 78 years) whose blood pressure control was inadequate with either beta-blocker or diuretic monotherapy were studied in a randomized, prospective double-blind comparison of atenolol (50 mg), amiloride (5 mg) with hydrochlorothiazide (50 mg), and these two treatments combined. Blood pressures were measured at least 24 hours after a single daily dose. The combined therapy was more effective in reducing lying (p less than 0.01) and standing (p less than 0.05) systolic blood pressure than either beta-blocker or diuretic alone. Combined therapy was more effective than diuretic on lying (p less than 0.05) or standing blood pressure (p less than 0.01). There was little difference in blood pressure control between beta-blocker and diuretic therapy. Side-effect complaints were similar on beta-blocker (5 complaints) and diuretic (7) and appeared to be additive on combined treatment (12). Diuretic treatment alone or in combination after the 1-month randomized periods produced shifts in some biochemical parameters (creatinine, urea, urate, sodium) in this older population of treated hypertensives, but clinically significant alteration in serum potassium levels was not seen.

Adrenergic beta-Antagonists↗

A new diuretic that does not reduce renal handling of uric acid in rats, S-8666.

The uric acid-retaining effects of diuretics were studied using sodium-restricted spontaneously hypertensive rats. Test agents were administered orally once a day for two weeks. Diuretic thiazides such as trichlormethiazide and hydrochlorothiazide and loop diuretics such as furosemide and indacrinone clearly reduced the renal function for uric acid excretion in treatment which produced major effects such as diuresis, saluresis and hypotension. However, a new diuretic with uricosuric activity, S-8666, developed in our laboratories, had no effect on the renal handling of uric acid at doses which showed major effects similar to those of other diuretics. The results should aid the understanding of the utility of S-8666 as a new diuretic antihypertensive which does not cause hyperuricemia during therapy.

Animals↗

Comparison of long-term therapeutic effect of an ACE inhibitor, temocapril, with that of a diuretic on microalbuminuria in non-diabetic essential hypertension.

Many investigators have reported that angiotensin-converting enzyme (ACE) inhibitors have antiproteinuric effects and retard the progression of renal impairment in diabetic patients. On the other hand, those effects of ACE inhibitors have not been well established in patients with essential hypertension. This study was conducted to prospectively evaluate whether an ACE inhibitor, temocapril, could modify the urinary microalbumin excretion rate (UAE) in hypertensive outpatients who had no signs of renal impairment. To compare the long-term effect of temocapril with that of a diuretic on UAE, hypertensive patients treated with a diuretic (trichlormethiazide) were enrolled in a prospective study if they had normal serum creatinine levels and no overt proteinuria during a 3-month screening period. A urinary microalbumin-to-urinary-creatinine ratio (mg albumin/mmol Cr) was used as an estimate of UAE. Patients visited the hospital monthly to determine blood pressure (BP) and UAE. After baseline observation during the treatment with the diuretic, the subjects were randomly divided into two groups. In group A, the diuretic was switched to temocapril, 2 to 4 mg once daily for 12 months. In group B, the subjects continued to receive the diuretic for an additional 12 months. Seventy-six outpatients (41 men and 35 women; mean age, 59.0+/-1.4 years) with essential hypertension entered the study. The effects of temocapril on BP appeared to be clinically similar to those of the trichlormethiazide, but the use of temocapril significantly decreased UAE. In group A (n=37), UAE decreased significantly (p<0.01) from the baseline value of 4.19+/-0.37 mg albumin/mmol Cr to 2.47+/-0.29 and 2.68+/-0.28 mg albumin/mmol Cr at the 6th and 12th month of temocapril therapy, respectively. In contrast, in group B (n=39) UAE was unchanged (baseline, 4.16+/-0.63 mg albumin/mmol Cr; 6 months, 4.92+/-0.72; 12 months, 4.71+/-0.74). These results indicate that long-term therapy with temocapril may be superior in reducing UAE than is diuretic therapy in patients with essential hypertension who had no signs of renal impairment.

Albuminuria↗

Tolerability and safety of a calcium channel blocker in comparison with a diuretic in the treatment of elderly patients with hypertension: secondary analysis of the NICS-EH.

A randomized prospective controlled study, the National Interventional Cooperative Study in Elderly Hypertensives (NICS-EH), previously demonstrated that the preventive effect of the long-acting calcium channel blocker nicardipine on the cardiovascular endpoint was similar to that of the diuretic, trichlormethiazide. The present report is a sub-analysis in which we compare the tolerability and safety of the calcium channel blocker with that of a diuretic in the long-term treatment of elderly hypertensives. A total of 429 elderly patients with hypertension were assigned to the nicardipine group or the diuretic group by the double-dummy method and were followed up for 5 years. Two hundred four patients in the nicardipine group and 210 patients in the diuretic group were analyzed. The incidences of fatal and nonfatal cardiovascular (CV) events in the two groups were comparable, and there was no significant difference in the cumulative event-free rate. However, the total incidence of adverse reactions, including non-CV events and unfavorable BP changes, was 31 cases (15.2%) in the nicardipine group, which was significantly lower than the 47 cases (22.4%) in the diuretic group (log-rank: p=0.026, G. Wilcoxon: p=0.01). The total number of medical endpoints, including CV events, the withdrawal of the patient from the study, was 52 (25.5%) in the nicardipine group, which was significantly lower than the 65 (31.0%) in the diuretic group (log-rank: p=0.078, G. Wilcoxon: p=0.044). It was concluded that sustained-release nicardipine is better tolerated, as it exhibits a lower incidence of medical-related withdrawals such as adverse drug reactions, non-cardiovascular events and unfavorable BP responses during the treatment.

Aged↗

Loop diuretics increase bone turnover and decrease BMD in osteopenic postmenopausal women: results from a randomized controlled study with bumetanide.

UNLABELLED: To study effects of loop diuretics on bone, 87 women were randomized to 1 year of treatment with bumetanide or placebo. Compared with placebo, bumetanide decreased BMD by 2% at the total hip and by 1.4% at the whole body. Levels of biochemical bone markers were lower in the placebo than in the bumetanide group. Thus, treatment with loop diuretics affects bone metabolism. INTRODUCTION: Loop diuretics may affect bone because they increase the renal calcium excretion and alters the diurnal rhythm of plasma PTH levels. We studied the effects of 1 year of treatment with the loop diuretic bumetanide on bone metabolism. MATERIALS AND METHODS: In a double-blinded design, 87 healthy postmenopausal women with osteopenia were randomized to 1-year bumetanide treatment 2 mg/day or placebo. BMD, plasma levels of calcitropic hormones, and biochemical bone markers were measured at baseline, after 1 year of treatment (week 52), and 6 months after withdrawal of treatment (week 78). Calcium (800 mg/day) and vitamin D (10 microg/day) were administered to all participants during the entire 1.5-year study period. RESULTS: Compared with placebo, urinary calcium (+17%) and plasma PTH levels (+9%) increased significantly in response to bumetanide. After 1 year of treatment, BMD in the bumetanide compared with the placebo group was significantly decreased by 2% at the total hip and ultradistal forearm and by 1.4% at the whole body. In addition, levels of biochemical markers of bone turnover differed significantly (approximately 20%) between groups, with lower levels in the placebo than in the bumetanide group. Six months after the end of treatment, the effects of bumetanide were weakening. CONCLUSIONS: Treatment with loop diuretics affects bone turnover and decreases BMD. Further studies may reveal whether loop diuretics should be considered as a risk factor for fracture.

Aged↗

Association between adherence to diuretic therapy and health care utilization in patients with heart failure.

STUDY OBJECTIVE: To determine the relationship between adherence to diuretic therapy and health care utilization. DESIGN: Prospective, observational study. SETTING: University-affiliated medical center. PATIENTS: Forty-two patients with heart failure. INTERVENTION: Electronic monitoring of adherence to diuretic therapy (percentage of diuretic prescription container openings) and to scheduling (percentage of container openings within a specific time). MEASUREMENTS AND MAIN RESULTS: All patients were prescribed a diuretic, most commonly furosemide (88%). Patients varied widely in adherence to therapy (mu = 72% +/- 30%) and to scheduling (mu = 43% +/- 30%). Education was a predictor of drug-taking adherence (p=0.0062) but not of scheduling adherence. Log-linear models revealed that poor scheduling adherence was associated with increased cardiovascular-related hospitalizations (chi2 11.63, p=0.0006) and predicted more heart failure-related hospitalizations (chi2 4.04, p=0.0444). In contrast, neither measure was significantly associated with cardiovascular- or heart failure-related emergency department visits. We found a moderate correlation between scheduling adherence and taking adherence (r = 0.6513). CONCLUSION: Patients taking a greater proportion of diuretic agents on schedule may decrease the risk of cardiovascular- and heart failure-related hospitalizations. If these findings are confirmed by a larger study, interventions to improve adherence and patient health outcomes should consider the timing of doses as well as the number of daily doses of a diuretic.

Diuretics↗

Adverse effects of diuretics.

Analysis of the available evidence indicates that diuretics do not increase coronary heart disease morbidity and mortality. The multiclinic trials supporting the cardiotoxicity hypothesis are few in number and flawed in design. The majority of the trials, including the well designed trials, indicate no excess of coronary heart disease (CHD) events in diuretic-treated patients compared with those given other drugs or placebo. Recent studies indicate no increase in cardiac arrhythmias after diuretic treatment. Also, although depletion of intracellular potassium and magnesium occurs in patients with congestive heart failure even without diuretics, intracellular concentration of these ions is not significantly reduced by diuretics in patients with uncomplicated hypertension. Modest elevations of serum cholesterol may occur during the first 6 to 12 months of treatment with thiazide diuretics. However, after this time these elevations fall to or below the pretreatment level. The fall may be greater in patients receiving other drugs but the differences are small and their clinical significance is questionable. The incidences of hyperglycaemia and diabetes were only minimally increased in long term clinical trials while the importance of hyperinsulinism and insulin resistance in causing CHD remains unproven in patients. Thiazides remain, therefore, a safe and effective treatment for patients with hypertension.

Diuretics↗

Optimising diuretic therapy in elderly patients with hypertension.

Hypertension is the most important risk factor for cardiovascular events in the elderly and it is present in more than 50% of acculturated populations over 60 years of age. Morbidity trials have clearly demonstrated the benefits of treating hypertension in the elderly in all subgroups examined, including diabetics, those over 80 years of age, those with or without electrocardiographic abnormalities, and in both men and women. These reductions in strokes, coronary events, and other hypertensive complications have been seen primarily with diuretic-based regimens, with or without potassium-sparing therapy. However, in the 1990s physicians are initiating diuretics less often for older patients with hypertension in spite of this scientific evidence. Low doses of diuretics have been well tolerated, successful in recent morbidity trials, and avoid much of the concerns about theoretical toxicities from diuretics, although higher doses have also been shown to reduce cardiovascular events. Until calcium channel blockers, angiotensin converting enzyme inhibitors, alpha-blockers, or some other class of antihypertensive agent has been demonstrated to be at least as effective as diuretics in reducing cardiovascular events or mortality, diuretics should be the first drug class to consider for the treatment of hypertension in the elderly.

Aged↗

Resistance to diuretics: emphasis on a pharmacological perspective.

Resistance to diuretics occurs frequently in clinical settings. Most attention to this phenomenon has been directed toward the pathophysiology of the disease state, with little focus on the pharmacology of the diuretics themselves. This review summarises the pathogenesis and emphasises the pharmacological determinants of response to diuretics, including absorption, delivery to the kidney, and response to amounts of diuretic reaching the site of action. In normal subjects, overall response to organic acid diuretics such as frusemide (furosemide) is determined by the total amount of drug delivered into the urine (reflecting amounts of drug reaching the intraluminal site of action), the time course of delivery, and the relationship between amounts of drug reaching the urine and response (the dynamics of response). The conditions of azotaemia, inhibition of synthesis of prostaglandins, and the oedematous disorders of congestive heart failure, cirrhotic liver disease and nephrotic syndrome are examined in the above context. In azotaemic subjects, delivery of organic acid diuretics to their intraluminal site of action is inhibited by accumulated endogenous organic acids which compete for transport into the nephron at the organic acid secretory site of the proximal tubule. Whether the dynamics of response are changed has not been investigated. During inhibition of synthesis of prostaglandins, and in the oedematous disorders, there appear to be no changes in handling of frusemide; i.e. bioavailability, total drug delivered into the urine and the time course of delivery are comparable with that in normal subjects unless concomitant renal dysfunction exists. Resistance in these conditions is therefore due to a change in the dynamics of response.

Diuretics↗

Diuretic-induced magnesium losses.

Long term administration of common loop or distal tubular diuretics may cause somatic magnesium depletion. The resultant deficiency of Mg++ destabilises the myocardium electrically and is a principal cause of cardiac arrhythmias ascribed to diuretics. The adverse effects of diuretics caused by Mg++ depletion can be avoided by selecting diuretics that do not cause magnesium deficiency, minimising the diuretic dose, supplementation of Mg++ intake, or the concomitant use of a K+-retaining, Mg++-sparing diuretic.

Diuretics↗

Acute and long term effects of loop diuretics in heart failure.

Diuretics, together with digitalis glycosides and vasodilators are of prime importance in the medical treatment of patients with congestive heart failure (CHF). Diuretics provide quick symptomatic relief in these patients. Their beneficial effect is related to the promotion of sodium and water excretion via the kidney, thus reducing extracellular fluid volume expansion and mitigating the increase in preload and afterload caused by sodium and water retention. Loop diuretics administered intravenously are indispensable in the management of pulmonary oedema; thiazides and loop diuretics in low doses are effectively used in the oral treatment of mild to moderate heart failure. Torasemide is a new loop diuretic which differs from furosemide (frusemide) and related loop diuretics by virtue of its longer elimination half-life and longer duration of action, with almost complete bioavailability. The efficacy and tolerability of torasemide have been compared with furosemide in several studies. Once daily oral administration of torasemide (starting with 5mg) or furosemide 40mg reduce bodyweight, oedema and symptoms of heart failure to a similar extent. Mean New York Heart Association class is consistently reduced by 0.5 to 0.7. Intravenous administration attenuates the increase in intracardiac pressures during exercise in patients with CHF, and produces acute improvements in cardiac haemodynamics in patients with high grade left heart failure. A beneficial effect on both pulmonary and cardiac haemodynamics has been demonstrated during chronic oral treatment of patients with previously untreated CHF. Torasemide was well tolerated with only mild and transient adverse effects reported in a small number of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Diuretics↗

Potassium supplements and potassium-sparing diuretics. A review and guide to appropriate use.

Epidemiological and clinical studies suggest that low dietary potassium intake may have an important role in determining the development of diseases such as hypertension, and perhaps even stomach cancer, and that increased potassium intake may have beneficial effects in several other conditions. Dietary adjustment or active potassium supplementation has been suggested as a natural, less costly and safe method of increasing potassium levels, although active supplementation with tablets or solutions is not recommended in healthy people with normal serum potassium levels. However, increasing dietary potassium intake in the elderly and in patients with renal impairment must be considered with caution. Diuretics have a long established role in the management of hypertension and heart failure. There is no convincing evidence to suggest that the small reduction in plasma potassium levels associated with low dose thiazide and loop diuretic therapy needs to be routinely prevented by the use of potassium-sparing drugs. In non-digitalised patients little association has been found between mild diuretic-induced hypokalaemia and arrhythmias. Thus, the routine prophylactic use of potassium-sparing diuretics in combination with non-potassium-retaining diuretics for the treatment of hypertension and oedematous states is not justified. Based on current evidence, treating all patients whose serum potassium level decreases below 3 mmol/L is recommended, although for certain patients at particular risk of hypokalaemia, levels may need to be maintained above 3.5 mmol/L. In overt hypokalaemia, several therapeutic options are available to the clinician. These include increased consumption of potassium-rich foods, the use of salt substitutes, medicinal potassium supplementation or distal tubular (potassium-sparing) diuretics.

Administration, Oral↗

Clinical pharmacology of diuretics.

Diuretics belong to the drugs most frequently used. Thiazide diuretics, loop diuretics and potassium sparing diuretics are the agents with practical significance. Many data concerning the pharmacokinetics of these drugs have been reported. Nevertheless, the metabolism of some diuretics is not yet fully elucidated. There are numerous pharmacodynamic drug interactions with diuretics which in general can be predicted from the spectrum of pharmacodynamic actions of the drugs involved.

Canrenoic Acid↗

Diuretics and risk of sudden death in hypertension--evidence and potential implications.

Randomized trials have produced solid evidence that non potassium-sparing diuretic therapy in hypertension is beneficial, but the controversy regarding the possibility that these drugs may increase the risk of sudden death in some patients continues. Although few sudden deaths were reported in the trials, findings indicate that an excess risk of sudden death in users of these diuretics exists (pooled risk ratio 1.5; 95% CI 1.1-2.0). Two recent case-control studies provide consistent evidence that non potassium-sparing diuretics are associated with a twofold risk of sudden death compared to potassium-sparing diuretic therapy. It is estimated that among the 400,000 men and 1,000,000 women treated for hypertension in the Netherlands, such as excess risk would lead to respectively 96 and 34 cases of sudden death. We conclude that the available evidence strongly suggests that hypertensive patients on non potassium-sparing diuretic therapy are at an increased risk of sudden death. Concomitant prescription of potassium-sparing diuretic agents should be considered in these patients.

Case-Control Studies↗

Comparison of indapamide with thiazide diuretics in patients with essential hypertension.

The effect of the new diuretic antihypertensive drug, indapamide (2.5 mg a day), was compared with the effect of thiazide diuretics in 24 patients with hypertension (seven of whom were receiving a diuretic alone, six were taking a beta-blocker plus a diuretic, and 11 received other combinations of drugs, including a diuretic in all cases). The randomized crossover study with two six-week phases indicated that indapamide is an effective hypotensive agent with potency similar to that of the thiazide diuretics in lowering the blood pressure and in increasing the excretion of potassium.

Benzothiadiazines↗