Diuretic Therapy For Hypertension Research Articles

Effect of diuretics on plasma aldosterone and potassium in primary hypertension: A systematic review and meta-analysis.

By contrast with drugs inhibiting the renin-angiotensin-aldosterone system (RAAS), diuretics stimulate renin release by the kidneys. Although plasma aldosterone (PA) is thought to be mainly regulated by RAAS activity, serum potassium has been shown to be an important factor in animal models and humans. Here we perform a systematic review and meta-analysis of randomised controlled trials (RCT) in hypertension investigating the effects of diuretic therapy on PA and the correlation of change in PA with that of potassium and blood pressure (BP). Three databases were searched: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). Titles were first screened by title and abstract for relevance before full-text articles were assessed for eligibility according to a predefined inclusion/exclusion criteria. A total of 1139 articles were retrieved, of which 42 met the prespecified inclusion/exclusion criteria. The average standardised difference in mean PA was similar for all classes of diuretic: thiazide/thiazide-like 0.299 (95% confidence interval [CI] 0.150, 0.447), loop 0.927 (0.37, 1.49), MRA/potassium-sparing 0.265 (0.173, 0.357) and combination 0.466 (0.137, 0.796), Q = 6.33, P = .097. In subjects untreated with another antihypertensive, there was a significant relationship between change in PA and change in systolic BP but no relationship with the change in potassium. In RCTs of diuretic therapy in hypertension, there is an increase in PA with all classes of diuretic and no significant between-class heterogeneity. Change in PA is not related with potassium but correlates with the change in BP in subjects untreated with another antihypertensive medication.

The Choice of Thiazide Diuretics

Thiazide diuretics were introduced in the United States for the treatment of hypertension in 1957. The first of these, chlorothiazide, was soon accompanied by a large number of other sulfonamide derivatives, including chlorthalidone. Hydrochlorothiazide (HCTZ) rapidly became the most commonly prescribed antihypertensive drug in the United States, whereas bendroflumethiazide was most popular in the United Kingdom. The initial popularity of HCTZ in the United States was abetted by its use in the first controlled trial of the treatment of nonmalignant hypertension, the Veterans’ Affairs Cooperative Study.1 The starting dose of HCTZ was 50 mg/d, and it was used along with reserpine and hydralazine. A number of other trials published in the 1970s all used higher doses of diuretic, for example, ≥50 mg of HCTZ per day.2 For reasons unknown to me, chlorthalidone was chosen to be the diuretic in the first large controlled trial of the treatment of hypertension, the Hypertension Detection and Follow-Up Program.3 In the Hypertension Detection and Follow-Up Program, all 10 940 patients were started on chlorthalidone from 25 to 100 mg/d. Other drugs were added to achieve control of the blood pressure. In addition, half were assigned to “referred” care and the other half to more closely monitored and intensively treated “stepped” care. The stepped care–treated half achieved a 4.4% further reduction in diastolic blood pressure and a 17.0% reduction …

Primary Aldosteronism Associated with Severe Rhabdomyolysis Due to Profound Hypokalemia

A 55-year-old Japanese man was admitted to our hospital with severe weakness. Without measurement of serum electrolyte concentrations, diuretic therapy for hypertension was started 2 weeks prior to admission. Laboratory findings showed profound hypokalemia (1.4 mEq/L), and extreme elevation of the serum creatinine phosphokinase levels (15,760 IU/L), suggesting that the patient had hypokalemic paralysis and hypokalemia-induced rhabdomyolysis. Further evaluations, including adrenal venous sampling strongly suggested that he had primary aldosteronism. He was treated successfully by laparoscopic adrenalectomy. This case provides an important lesson that serum electrolyte concentrations should be measured in hypertensive patients before the administration of antihypertensive agents.

Biochemical and etiological characteristics of acute hyponatremia in the emergency department

Hyponatremia can be classified as acute or chronic depending on its duration, and treatment options are tailored to this classification. However, it is sometimes difficult to differentiate acute from chronic hyponatremia in the Emergency Department (ED). The objective of this study was to identify characteristics to help diagnose and manage acute hyponatremia in the ED. Patients with acute hyponatremia in the ED were enrolled from a retrospective 2-year chart review. Eleven patients (0.8%) were identified with acute hyponatremia out of a total of 1321 hyponatremic patients. There were nine women and two men. The mean age was 48.9 years. The mean sodium (Na +) level was 115 ± 4 mmol/L. Accompanying biochemical abnormalities included hypouricemia and hypouremia with increased fractional excretions of uric acid (UA) and urea. The estimated amount of water intake ranged from 2.5 to 10 liters (mean, 5.1 ± 2.3 liters) during the day before ED presentation. All patients were treated with hypertonic saline and furosemide at a correction rate of 1.6 ± 0.5 mmol/L/h. No patients had neurological sequelae after treatment. The causes of acute hyponatremia included induction of abortion with oxytocin (n = 1), primary polydipsia on neuroleptic agents (n = 2), polyethylene glycol (PEG) preparation for colonoscopy (n = 1), diuretic therapy for hypertension (n = 4), ecstasy use (n = 1), and weight-reducing herbal teas (n = 2). We conclude that in the right clinical setting, high free water intake and low serum urea and UA favor acute hyponatremia. A detailed drug history may be helpful in the differential diagnosis of acute hyponatremia.

Are prescribing patterns of diuretics in general practice good enough?: A report from the Møre & Romsdal Prescription Study

Objective-To examine general practitioners' (GPs) prescribing patterns of diuretics with respect to indications, drugs and doses to reveal possible needs for prescribing audits.Design - Observational, cross-sectional study.Setting - The Norwegian county Møre & Romsdal.Subjects - 1896 prescriptions for diuretics prescribed by GPs during two months.Main outcome measures - Prescriptions (drugs, strength of tablets, volume prescribed, directions for use). Diagnoses for prescribing.Results - Furosemide was prescribed most frequently (48.7%) followed by the compound diuretic of hydrochlorothiazide and amiloride (26.4%), thiazides and related drugs (13.0%), and spironolactone (5.8%). Diuretics were mainly prescribed for hypertension (48.4%), congestive heart failure (35.6%), and oedemas (e.g. orthostatic) (6.1%). The patients' mean age was 69.2 years; two of three were females.When thiazides and related drugs were prescribed for hypertension, we found that the daily dose was excessive in 37.2% of the cases.In congestive heart failure, furosemide was prescribed in about four of five cases, while bumetanide was prescribed in 1.5% of the cases.Conclusion - Our findings indicate that GPs need more knowledge about low-dose diuretic therapy in hypertension, about different diuretic regimens in heart failure, and about non drug treatment for orthostatic oedema. Clinical pharmacology regarding diuretics should be given priority in the vocational training and continuing education for GPs.

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.

Diuretic Therapy for Hypertension and the Risk of Primary Cardiac Arrest

Background The results of trials of the primary prevention of coronary heart disease have suggested that treating hypertension with high doses of thiazide diuretic drugs might increase the risk of sudden death from cardiac causes. In contrast, treatment with low doses of thiazide reduces the risk of coronary heart disease. Methods To examine the association between thiazide treatment for hypertension and the occurrence of primary cardiac arrest, we conducted a population-based case-control study among enrollees of a health maintenance organization. The case patients were 114 persons with hypertension who had a primary cardiac arrest from 1977 through 1990. The control patients were a stratified random sample of 535 persons with hypertension. The patients' treatment was assessed with the use of a computerized pharmacy data base. Records of their ambulatory care were reviewed to determine other clinical characteristics. Results The risk of primary cardiac arrest among patients receiving combined thiazide an...

Diuretic Therapy for Hypertension and the Risk of Primary Cardiac Arrest

Diuretic Therapy for Hypertension and the Risk of Primary Cardiac Arrest

Diuretic therapy for hypertension and the risk of primary cardiac arrest.

The results of trials of the primary prevention of coronary heart disease have suggested that treating hypertension with high doses of thiazide diuretic drugs might increase the risk of sudden death from cardiac causes. In contrast, treatment with low doses of thiazide reduces the risk of coronary heart disease. To examine the association between thiazide treatment for hypertension and the occurrence of primary cardiac arrest, we conducted a population-based case-control study among enrollees of a health maintenance organization. The case patients were 114 persons with hypertension who had a primary cardiac arrest from 1977 through 1990. The control patients were a stratified random sample of 535 persons with hypertension. The patients' treatment was assessed with the use of a computerized pharmacy data base. Records of their ambulatory care were reviewed to determine other clinical characteristics. The risk of primary cardiac arrest among patients receiving combined thiazide and potassium-sparing diuretic therapy was lower than that among patients treated with a thiazide without potassium-sparing therapy (odds ratio, 0.3; 95 percent confidence interval, 0.1 to 0.7). As compared with low-dose thiazide therapy (25 mg daily), moderate-dose therapy (50 mg daily) was associated with a moderate increase in risk (odds ratio, 1.7; 95 percent confidence interval, 0.7 to 4.5), and high-dose therapy (100 mg daily) was associated with a larger increase in risk (odds ratio, 3.6; 95 percent confidence interval, 1.2 to 10.8) (P value for trend, 0.02). The addition of a potassium-sparing drug to low-dose thiazide therapy was associated with a reduced risk of cardiac arrest (odds ratio, 0.4; 95 percent confidence interval, 0.1 to 1.5). Both the dose of thiazide drugs and the addition of potassium-sparing drugs influence the risk of primary cardiac arrest. These results may explain the differences in the effect of antihypertensive therapy on mortality from coronary heart disease in previous clinical trials.

Diuretic therapy for hypertension was associated with increased mortality in patients with diabetes

Source Citation Warram JH, Laffel LM, Valsania P, Christlieb AR, Krolewski AS. Excess mortality associated with diuretic therapy in diabetes mellitus. Arch Intern Med. 1991 Jul;151:1350-6.

Arrhythmias, electrolytes, and ACE inhibitor therapy in the elderly.

Elderly patients have a higher incidence of symptomatic cardiac arrhythmias and greater management problems than younger patients. This is due to the frequency of occult and overt cardiovascular disease, reduction in cardiac reserve as a consequence of the aging process, and coexistence of other disorders which provide a substrate for iatrogenic disease. The last problem is largely due to electrolyte disturbances induced by diuretic therapy for hypertension and heart failure. The major electrolyte disturbance implicated in arrhythmogenesis is diuretic-induced hypokalemia. There is no doubt that arrhythmias are caused by severe hypokalemia (less than 2.5 mEq/l), or by a milder degree of hypokalemia in digitalis-treated patients or those with left ventricular hypertrophy, but the literature contains conflicting data regarding the importance of milder hypokalemia. The most compelling study in support of its importance used a crossover study design in hypertensive patients with coronary disease and showed that mild degrees of hypokalemia induced by thiazide diuretics increased the tendency to arrhythmia when compared with normokalemia on a potassium-sparing diuretic. Diuretic-induced magnesium deficiency is also regarded by some to be as important as hypokalemia, but the evidence is less extensive. Thus, it appears reasonable to avoid hypokalemia and hypomagnesemia. The optimum therapeutic approach in using diuretics is to keep the dose as low as possible, restrict dietary sodium, and add potassium supplements. Since, in many cases of hypertension, hypokalemia is due to secondary hyperaldosteronism, the use of angiotensin-converting enzyme inhibitors is another therapeutic approach that is effective in hypertension and heart failure.

Altered Adrenergic Control in Hypercholesterolemia

Vascular reactivity is altered by hypercholesterolemia and atherosclerosis. Animal studies have shown that serotonergic mechanisms of vasoconstriction are enhanced, while the changes with adrenergic mechanisms are still equivocal. Serum lipids are increased with beta-blocker and diuretic therapy for hypertension. Thus, the increase in serum lipids may be responsible for both structural and functional abnormalities of the vascular system in hypertensive patients. In contrast, recent reports have suggested that alpha 1-adrenergic receptor inhibition, useful in hypertension therapy, may exert a beneficial effect on plasma lipids. We have also collected preliminary data in our laboratory examining the effects of alpha 1-adrenergic receptor inhibition with prazosin on plasma cholesterol levels and vascular reactivity in monkeys with hypercholesterolemia. We observed large reductions in both total cholesterol and the very-low-density lipoprotein (VLDL) + low-density lipoprotein (LDL) fraction of cholesterol in these animals during treatment with prazosin. Thus, in addition to its sympatholytic action on the vasculature, alpha 1-adrenergic receptor inhibition appears to exert a beneficial effect in reducing total cholesterol levels.

Potassium loss, ventricular irritability, and the risk of sudden death in hypertensive patients.

In the past, potassium depletion in both non-digitalised patients and in patients without cardiac disease was thought to cause no adverse cardiac effects. However, several studies have now demonstrated a significant incidence of ventricular ectopic activity (VEA) with diuretic-induced hypokalaemia, even in hypertensive patients without overt heart disease. Additional evidence suggests that sudden death may occasionally result from this VEA. Potassium repletion with potassium-sparing diuretics or with potassium chloride supplementation has generally demonstrated a beneficial therapeutic effect in reducing VEA. However, after diuretic therapy occasional patients may have persistent VEA which may result from focal myocardial lesions associated with potassium depletion. In contrast, diuretic therapy in which normokalaemia is maintained has only been associated with a very low occurrence of VEA. Thus, with the preservation of normokalaemia, diuretic therapy for hypertension does not appear to be associated with the significant hazards of VEA.

Hemodynamic effects of diuretic therapy in hypertension.

The antihypertensive effect of diuretics is well documented. At least some preserved kidney function seems to be necessary to achieve a demonstrable effect. The importance of fluid volume reduction for the antihypertensive effect of these drugs during long-term treatment is however uncertain. The effects on central hemodynamics vary according to the literature, but the blood pressure reduction in responders (delta MAP greater than 10%) may primarily be explained by a reduction of the total peripheral vascular resistance. The peripheral circulation is influenced in the same way. Sometimes a flow reduction is observed, and sometimes a resistance reduction. In spite of a lasting blood pressure reduction after treatment with diuretics, the structural hypertensive vascular changes do not seem to be influenced.

Diuretic therapy for mild hypertension: The “real” cost of treatment

The benefit of any medical intervention, particularly drug therapy, must be weighed against its cost. These costs are not only dollar expenditures but effects on lifestyle and overall health. Diuretic therapy for hypertension has been in use long enough to allow long-term clinical evaluation. It is clear from the numerous prospective drug intervention trials involving hypertensive patients that diuretic therapy is not free of “costs.” Aside from the fact that 15 to 20% of diuretic-treated patients reportedly drop out of trials because of side effects, including exertional dyspnea, fatigability, lethargy and impotence, numerous metabolic derangements have been reported with these drugs, i.e., potassium, uric acid, lipid, sodium, glucose and magnesium alterations. Perhaps most important are the changes in lipid fractions, which may be responsible for the failure of antihypertensive therapy to decrease the risk of coronary heart disease. Thus, although diuretics are somewhat less expensive than other antihypertensive drugs in terms of dollars, their overall costs are high. The major alternatives, such as the α-blocker prazosin or the central nervous system agent clonidine, are preferable, do not impair a patient's lifestyle and are recommended to be used along with changes in diet and an exercise program for control of mild to moderate hypertension.