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PubMed1989

Secretagogues increase apical membrane conductance of isolated bullfrog corneal epithelium pretreated with loop diuretics.

Bullfrog (Rana catesbeiana) corneas were mounted in an Ussing type chamber and impaled with an intracellular microelectrode and the short circuit current was inhibited by pretreatment with the loop diuretics furosemide (0.3 to 1 mM) or bumetanide (10 to 100 microM). Subsequent addition of the secretagogues prostaglandin E2, forskolin, or 3-isobutyl-1-methylxanthine (IBMX) caused the fractional voltage drop of the apical barrier to decrease from 0.72 +/- 0.05 to 0.48 +/- 0.04 and the chloride-dependent conductance to increase by 0.15 +/- 0.03 mS/cm2, but caused only a small, transient increase in short circuit current. The loop diuretics by themselves always greatly reduced the short circuit current but did not consistently reduce conductance or fractional voltage drop of the apical membrane. Because the secretagogues were able to increase the apical membrane conductance of diuretic-inhibited corneas without large effects on the short circuit current, the loop diuretics must have a major effect at a site other than the apical membrane Cl- conductance, presumably at the basolateral membrane. An additional effect of the loop diuretics at the apical membrane is also possible.

1-Methyl-3-isobutylxanthine↗
PubMed1975

Effects of certain diuretics on the electrophysiological characteristics of the nephron in the rat kidney.

Electrophysiological micropuncture techniques were used to study the effect of certain diuretics on transtubular transport of electrolytes in the rat kidney. The mercurial diuretic novurite caused a reduction of active sodium transport in the proximal tubule, measured by short-circuit current and increased permeability of the tubular wall to ions which led to a considerable drop in transtubular potential and transepithelial resistance. Ethacrynic acid decreased the short-circuit current in the proximal tubule, without changing the permeability characteristics of the nephron. Xanthine diuretic euphylline did not reduce the short-circuit current in the proximal segment of the nephron; however, it increased the transepithelial potential of the renal tubule. In the distal tubule, euphylline and ethacrynic acid increased the difference in transtubular potential, whereas novurite reduced the transtubular potential. An increase in the electrical gradient of the distal tubule as a result of euphylline and ethacrynic acid action may be responsible for increasing potassium excretion. A decrease of the transtubular potential in the potassium excretion under mercurial diuretic action. The reduction of tubular reabsorption as a result of diuretic action is due to drug effect on different levels of the transtubular-ion transport system.

Aminophylline↗
PubMed1986

The dependence on chloride ions of the loop diuretic sensitive component of passive sodium efflux from human red cells.

A study has been made of the passive (ouabain-insensitive) Na efflux from human red cells. The inhibition by loop diuretics (furosemide, piretanide and bumetanide) was additive with respect to ouabain and non-additive with respect to each other. They inhibited with high affinity in the sequence bumetanide greater than piretanide greater than furosemide. Passive Na efflux was not inhibited by amiloride, DIDS or SITS. In Cl-free media, Na efflux was reduced and there was no diuretic-sensitive component with any of the six Cl substitutes tested, except Br. The chloride concentration dependence of the diuretic-sensitive efflux was generally linear but saturable with sulphate and concave with acetate. In Na-free media, efflux was reduced, the apparent affinity for loop diuretics was lower and there was no chloride dependence. The diuretic-insensitive efflux was unaffected by anions in all conditions.

Anions↗
PubMed2004

Lessons from ALLHAT. Are low budget diuretics first line therapy in hypertension?

Diuretics are well-established and nowadays also cheap cardiovascular agents. In contrast to the most recent American hypertension guidelines (JNC 7) which ascribe a singular place to diuretics in the first-line treatment of hypertension following a one-sided interpretation of the ALLHAT results, in the balanced guidelines of the European Society of Hypertension (ESH) published in 2003, they are placed alongside beta-blockers, ACE inhibitors, sartans and calcium antagonists as the drugs of first choice, but not given preference. Previous scientific evidence and clinical experience is to a certain extent in line with this classification of diuretics. On the basis of the indisputable dose-dependent potential for side-effects such as hypokalaemia, diabetogenicity and stimulation of neurohumoural systems, I personally consider diuretics to be inferior to the more recent substance groups, particularly the RAS inhibitors. I would therefore welcome it if diuretics in the future were removed from the monotherapy of hypertension and offered from the outset as low-dosed combination partners for RAS inhibitors, beta-blockers and also calcium antagonists. In this role they could only do good and not cause any damage.

Antihypertensive Agents↗
PubMed2005

Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature.

UNLABELLED: Metolazone is a potent thiazide-like diuretic. It is recommended in severe congestive heart failure (HF). We conducted a review of the existing literature and found that the available information on the use of metolazone in HF is based on studies containing less than 250 patients in total. Nevertheless, metolazone is widely used, often in combination with a loop diuretic. Absorption of metolazone seems to be reduced in HF. Metolazone produces a diuretic response despite a low glomerular filtration rate. A wide dose range of metolazone has been investigated (< or =2.5 to 200 mg), leaving no clear dosing recommendation. However, in most studies a low starting dose (< or =5 mg) was used. We further report an observational study on 21 patients with refractory systolic HF from our specialized outpatient HF clinic. The aim was to evaluate the effects of metolazone in combination with a loop diuretic in contemporary HF patients. RESULTS: We registered 42 episodes of treatment with metolazone. The maximal dose of metolazone was 5 mg. NYHA functional class improved. A significant reduction during treatment in weight, blood pressure, plasma-sodium and -potassium was seen whereas plasma-BUN and -creatinine increased significantly. Clinically important hypokalemia (<2.5 mM) or hyponatremia (<125 mM) were observed during 10% of the treatment episodes. CONCLUSION: The literature review and the observational study support the use of low-dose metolazone (< or =5 mg) on top of oral loop diuretics, as an effective and relatively safe treatment in contemporary outpatients with refractory HF.

Aged↗
PubMed2006

Diuretic resistance in heart failure.

The use of diuretics for the treatment of heart failure (HF) is ubiquitous in any basic HF medical regimen. Although initially these drugs clearly show benefit by relieving symptomatic episodes of decompensated HF, long-term use of these drugs can lead to a "diuretic-resistant" state and is associated with an increased risk of morbidity and mortality. A number of factors may be responsible for this, including dietary noncompliance, inadequate diuretic dosing or methods of administration, and concomitant use of certain medications. Diuretics themselves may set in motion an iatrogenic cardiorenal syndrome leading to worsening renal function and diuretic resistance. The methods for overcoming this resistance are varied and require a focused approach with emphasis on relieving the congestive symptoms related to HF while attempting to preserve renal function and minimize any untoward systemic effects.

Diuretics↗
PubMed1983

Association of hyponatremia with increased renin activity in chronic congestive heart failure: impact of diuretic therapy.

A correlation between hyponatremia and increased plasma renin activity (PRA) has been reported in patients with severe congestive heart failure (CHF), implying both clinical and pathophysiologic significance. To determine the impact of diuretic therapy on this relation, we evaluated the correlation of serum sodium, prerenal azotemia (blood urea nitrogen/creatinine ratio [BUN/Cr] ), and PRA in 44 patients with severe CHF who were maintained on diuretic therapy. Serum sodium level was inversely related to PRA (r = -0.389, p less than 0.02). However, a significant correlation also existed between the BUN/Cr ratio and PRA (r = 0.365, p less than 0.025) and an inverse correlation between serum sodium level and the BUN/Cr ratio (r = 0.332, p less than 0.025). Multiple regression analysis of the 3 variables yielded significant interdependence (p less than 0.01). To evaluate the effect of diuretic therapy, 12 patients with severe CHF discontinued diuretic therapy and received, for 1 week each, 10 and 100 mEq sodium diets in balance studies. PRA ranged from 0.14 to 16 ng/ml/h. Despite this range, there was no significant correlation between either serum sodium or BUN/Cr ratio and PRA. It is concluded that the presence of marked hyponatremia and prerenal azotemia in patients with diuretic-treated CHF may suggest increased PRA. However, substantial patient-to-patient variability limits the predictive value of these correlations. Although some clinical value may be derived from such correlations, they should not be used to draw major inferences regarding the severity of CHF or the pathophysiology of water balance in CHF.

Adult↗
PubMed1990

Long-term diuretic therapy and renal function in essential arterial hypertension.

One of the main objectives of antihypertensive therapy is to preserve renal function from the deleterious effects of elevated blood pressure. Diuretics alone or in combination are effective for the treatment of arterial hypertension. Nevertheless, their use is accompanied by unwanted biochemical side effects, which have been attributed to their renal effects. During the last 10 years a group of 211 patients, diagnosed as having essential hypertension, were followed up. During the follow-up, they received a stepped-care therapeutic regimen consisting of nonpharmacologic measures (group 1), hydrochlorothiazide and amiloride (group 2), propranolol (group 3) and, if necessary, hydralazine (group 4). During the study, blood pressure remained within comparable, well-controlled levels in the 4 groups of patients. A progressive elevation of the levels of total serum cholesterol and glucose was observed in every group. The elevation attained statistical significance (p less than 0.01) after 4 years of therapy in those groups receiving the diuretic alone or in combination. Nevertheless, after 8 years of follow-up, the increment observed in these 2 parameters did not differ when patients in group 1 were compared with those in the remaining groups, indicating that thiazide diuretics could contribute to the earlier appearance of forthcoming events. Serum potassium levels were significantly lower (p less than 0.01) in groups 2 and 3 than in group 1. At the same time, we have observed the progressive appearance of clinically relevant proteinuria in 15.2% of patients, and the range of protein excretion ranged from 350 to 3,700 mg/24 hours. The appearance of proteinuria did not depend on the lack of control of blood pressure, nor on the different therapeutic requirements but was accompanied by a progressive decrease in creatinine clearance. The consequences of the renal effects of diuretics are of great importance during long-term therapy. The present results indicate that diuretics preempt the appearance of a forthcoming increase in serum glucose and cholesterol, and lessen the clinical relevance of these events.(ABSTRACT TRUNCATED AT 250 WORDS)

Diuretics↗
PubMed1990

Diuretics and the treatment of systemic hypertension.

Diuretics are still among the most frequently used antihypertensive drugs in the treatment of hypertension. Their pharmacologic and hemodynamic properties are based on the water and salt metabolism in the pathophysiology of high blood pressure. Initially, there is a reduction of plasma and extracellular fluid volume; cardiac output also decreases. After this early phase, cardiac output returns to normal with an accompanying decrease in peripheral resistance so as to correct the underlying hemodynamic fault of the hypertensive state. Diuretics have a high therapeutic efficacy either as monotherapy or in combination with beta blockers, angiotensin-converting enzyme inhibitors or calcium antagonists. The main problem with the use of diuretics is related to their metabolic side effects, which are dose-related. Currently, there is a tendency to administer low-dose diuretics, which result in fewer clinical and metabolic side effects, but with a continued antihypertensive efficacy. Therefore, low doses of diuretics can be recommended as initial therapy in the stepped-care approach of hypertension.

Diuretics↗
PubMed1990

Effects of a potassium-sparing/thiazide diuretic combination on cardiovascular reactivity to vasopressor agents.

The vascular effects of a diuretic combination (spironolactone/altizide) were studied in 5 anuric patients undergoing dialysis by measuring changes in cardiovascular reactivity to norepinephrine (NE) and angiotensin II (AII) after infusion of incremental doses of these 2 vasopressor agents. There was a marked dose-response relation between NE and AII administration and mean (NE) or diastolic (AII) blood pressure (BP). Diuretic treatment moderated the increase in mean or diastolic BP induced by NE or AII. In addition, the pressor doses of NE and AII, which are also parameters of vascular reactivity, were significantly increased after diuretic treatment (NE, +101%; AII, +163%). Right atrial and pulmonary capillary wedge pressures increased along with BP in response to NE. Diuretic treatment also moderated the increase in right atrial and pulmonary capillary wedge pressures induced by NE. These results suggest that the antihypertensive action of spironolactone and altizide in combination is mainly due to a direct effect on resistance and capacitance vessels. The mechanisms by which diuretics modify the cardioreactivity remain poorly understood; however, they may modify electrolyte transport (sodium and calcium) across vascular smooth muscle cell membranes or stimulate prostaglandin release.

Angiotensin II↗
PubMed1991

The relationship of sodium balance and concomitant diuretic therapy to blood pressure response with calcium channel entry blockers.

Marked heterogeneity exists in the response of blood pressure to specific antihypertensive agents. In general, a single therapeutic agent can be expected to provide an adequate blood pressure response in 40% to 60% of hypertensive patients. The addition of a second agent usually extends the response rate to over 85%. The addition of a diuretic to nondiuretic regimens often produces an additive blood pressure-lowering effect. However, calcium channel entry blockers (CCBs) may be an exception, as diuretics do not appear to improve these agents' efficacy. CCBs have a dual mechanism for blood pressure reduction. In addition to their vasodilatory actions, they also promote diuresis and natriuresis. These features account for the striking efficacy of these agents when used as monotherapy in hypertensive patients. Studies have shown that dietary sodium restriction does not appear to improve the efficacy of CCBs, nor is a high-salt diet predictive of a better therapeutic outcome. Recent studies also indicate that the addition of a diuretic to a CCB does not produce a significant or consistent additive antihypertensive effect. Because CCBs do not produce the typical responses of the renin-angiotensin-aldosterone (RAA) system to sodium/volume depletion, their diuretic and natriuretic effects do not result in the same adverse metabolic consequences as experienced with traditional diuretic therapy.

Blood Pressure↗
PubMed1991

Relationship between use of diuretics and continence status in the elderly.

Although diuretics have been implicated as a cause of urinary incontinence, no evidence has been presented prior to this report to confirm such a relationship. Our epidemiologic survey of 1,956 respondents sixty years of age and older in Washtenaw County, Michigan, revealed 24.6 percent of men and 36.9 percent of women were current users of a diuretic medication. Comparisons between users and non-users of diuretics and continence and incontinence status revealed no significant difference in the prevalence of incontinence in either gender. However, when male respondents who had cystometric examinations were analyzed, it was found that diuretic users who have uninhibited detrusor contractions (UDC) had a significantly higher prevalence of urinary incontinence (85.7%) when compared with non-users with UDC (25%) (p = 0.009). Among men who did not have UDC, use or non-use of diuretics showed a similar relationship but did not reach statistical significance (p = 0.085). There were too few female respondents with UDC to make meaningful analysis in this group.

Aged↗
PubMed2006

Thiazide diuretics for hypertension: prescribing practices and predictors of use in 194,761 elderly patients with hypertension.

BACKGROUND: Although several small studies have reported underuse of thiazide diuretics for elderly hypertensive patients, those factors which influence initial choice of first-line antihypertensive treatment are unknown. OBJECTIVES: : The objective of this study was to explore prescribing practices for antihypertensives in the elderly and determine which factors are associated with thiazide diuretic use as first-line treatment METHODS: This population-based cohort study used linked administrative databases for all elderly patients (> or =66 years of age) first treated for hypertension between July 1, 1994, and March 31, 2002, in Ontario, Canada. RESULTS: Of the 194,761 patients in our cohort, 68,858 (35%) were prescribed a thiazide diuretic as their first anti-hypertensive agent. On multivariate analysis, factors associated with being prescribed a thiazide as first-line treatment included age (adjusted odds ratio [AOR], 1.72 [95% CI, 1.67-1.78] for octogenarians compared with patients aged 66-69 years) and having multiple comorbidities (AOR, 1.24 [95% CI, 1.16-1.29] for Charlson scores of 2 and AOR, 1.52 [95% CI, 1.37-1.61] for Charlson scores of > or =3). On the other hand, men (AOR, 0.64 [95% CI 0.63-0.65]) and hypertensives with diabetes (AOR, 0.22 [95% CI, 0.21-0.23]) were substantially less likely to be prescribed thiazide diuretics as first-line treatment. Socioeconomic status was not associated with use of thiazide diuretics. CONCLUSIONS: One third of initial antihypertensive prescriptions for elderly patients were for thiazides in our publicly funded health care system with universal drug coverage. Socioeconomic status did not influence use of thiazides, but age, sex, and comorbidities did.

Aged↗
PubMed2005

Clinical and neurohumoral consequences of diuretic withdrawal in patients with chronic, stabilized heart failure and systolic dysfunction.

BACKGROUND: Loop diuretics are beneficial in heart failure in the short term because they eliminate fluid retention, but in the long-term, they could adversely influence prognosis due to activation of neurohumoral mechanisms. AIMS: To explore the changes induced by diuretic withdrawal in chronic nonadvanced heart failure. METHODS: Diuretics were withdrawn in 26 stabilized heart failure patients with systolic dysfunction (ejection fraction [EF]<45%). Clinical status was evaluated by physical exam, exercise capacity (corridor test) and New York Heart Association (NYHA) class. Biochemical and neurohumoral determinations were performed at baseline and at 3 months. RESULTS: At 3 months, 17 out of 26 patients (65%) were able to tolerate diuretic interruption without a deterioration in exercise capacity or New York Heart Association functional class. Renal function parameters improved (baseline urea 46.2+/-10.8 to 39.2+/-10.1 mg/dl at 3 months, p=0.014; creatinine 1.1+/-0.23 to 0.98+/-0.2 mg/dl, p=0.013). Glucose metabolism also improved (fasting glucose 151+/-91 to 122+/-14 mg/dl, p=0.035). Heart rate and systolic blood pressure did not significantly change, while diastolic blood pressure increased (from 80+/-10 to 87+/-13 mm Hg, p=0.006). Neurohumoral determinations showed a decrease in plasma renin activity (4.19+/-5.96 to 2.88+/-4.98 ng/ml, p=0.026), with no changes in aldosterone, arginine-vasopressin, endothelin-1 and norepinephrine. In contrast, atrial natriuretic peptide significantly increased (115+/-87 to 168+/-155 pg/ml, p=0.004). CONCLUSION: Diuretic withdrawal in stabilized heart failure with systolic dysfunction is associated with an improvement in renal function parameters, glucose metabolism and some neurohumoral parameters, such as plasma renin activity; however, atrial natriuretic peptide levels increased.

Adult↗
PubMed2006

Consumption and costs of antihypertensive drugs in Mexico: are diuretic agents a standing technological trajectory?

BACKGROUND: Little is known about hypertension medication consumption and costs in Mexico. Hypertension control is a pharmacological challenge and a public health issue. OBJECTIVE: (a) To compare drug sales, number of written prescriptions, and monthly treatment costs among 5 classes of antihypertensive drugs and (b) to analyze diuretic drug sales and prescriptions to determine whether these antihypertensive agents represent an established technological trajectory. METHODS: A retrospective time series data study from 1999 to 2003. Data sources used were International Marketing Services of Mexico drug sales and the Mexico Prescription Audit databases. The 5 different classes of antihypertensive drugs were accommodated into 4 main technological trajectories according to their main biological mechanisms of action. Each technological trajectory was assessed using consumption and prescription data. Daily defined dose was used to calculate drug treatment costs. RESULTS: The market for cardiovascular agents is one of the largest, and in 2003 accounted for a value market share of 59 billion US dollar and a unit share of 40.7 million. Among cardiovascular agents, antihypertensive drugs made up a large percentage of market shares. Calcium channel blockers and angiotensin-converting enzyme inhibitors I had the biggest share value of the total cardiovascular market. Amlodipine had the highest share among calcium channel blockers, and enalapril and captopril had the largest share among angiotensin-converting enzyme inhibitors I. The top-selling diuretic drug was furosemide. The trend in number of prescriptions was parallel to that in sales. The diuretic spironolactone was the most expensive drug treatment (59 US dollar). Treatment with spironolactone might represent 47% of the income of a Mexican family if their household income was close to minimum wage (124 US dollar). CONCLUSIONS: The most effective and least expensive drugs-diuretics-had the smallest market share of all antihypertensive agents in Mexico. Nevertheless, diuretic agents are still in use and kept over time a steady market share both in value and in units.

Adrenergic beta-Antagonists↗
PubMed1996

Combination therapy with diuretics: an evolution of understanding.

One of the current recommendations for the treatment of hypertension is a stepped-care approach in which a second drug is added to a first-line agent when adequate blood pressure control has not been achieved. It has been well demonstrated in multiple studies that the response rate to any single class of antihypertensive agent, given as monotherapy, is approximately 45-55%. Thus, in approximately half of the hypertensive population, a second drug will be required. This is not surprising, since it is now well recognized that hypertension is a multifaceted disease process. The use of combination therapy with low-dose diuretics (< 25mg hydrochlorothiazide [HCTZ] or its equivalent) has become a very attractive alternative choice to first-line therapy. The data from clinical trials clearly demonstrate that 6.25 mg or 12.5 mg HCTZ has an additive or synergistic effect on blood-pressure reduction when used in combination with most drugs. At low doses, the side-effect profile with diuretics is similar to placebo. Furthermore, metabolic side effects are significantly reduced when diuretics are used in low doses. The use of low-dose diuretics in combination with other first-line agents significantly enhances blood-pressure control and reduces the likelihood of adverse events and alteration in carbohydrate, lipid, and electrolyte metabolism. Thus, combination therapy with low-dose diuretics provides an attractive alternative approach to first-line treatment of essential hypertension.

Blood Pressure↗
PubMed1999

Urinary thiamine excretion in the rat: effects of furosemide, other diuretics, and volume load.

Long-term furosemide therapy is associated with increased urinary loss of thiamine. To examine the mechanism of furosemide-induced urinary thiamine loss, we measured urinary excretion of thiamine in rats in response to increasing doses of furosemide, acetazolamide, chlorothiazide, amiloride, mannitol, and extracellular fluid (ECF) volume loading by saline infusion. All animals were in normal thiamine balance as reflected by a thiamine pyrophosphate effect (TPPE) of 2.25% +/- 0.60% (mean +/- SEM), and all had normal renal function. Urinary flow increased in response to diuretic administration in a dose-dependent manner, reaching (mean) peak urinary flow rates of 283 to 402 microL/min. Fractional excretion of sodium (FE(Na)) exhibited the same pattern, reaching peak values of 12.3% to 23.2%. Urinary thiamine excretion increased in proportion to the incremental doses of diuretic agents, reaching (mean) maximal values of 7.44 to 9.34 pmol/min, with no significant difference (P = .11) between the various diuretics tested nor in response to saline loading. None of the diuretics tested differed in the effect on thiamine excretion, which was clearly flow dependent and only partially related to fractional sodium excretion. Urinary flow rate, being the single significant predictor, explained 78% (R2 = 0.78) of the variability in thiamine excretion rates. These findings indicate that urinary thiamine loss is caused by a nonspecific, flow-dependent mechanism common to all of the diuretics tested.

Animals↗
PubMed1988

Mineral excretion in premature infants receiving various diuretic therapies.

The association of various diuretic therapies with the renal handling of minerals, important factors in the development of nephrocalcinosis and osteopenia, was studied in low birth weight infants. Twenty-four-hour urine specimens (n = 65) were collected from 30 patients who were treated with (1) furosemide with or without spironolactone and hydrochlorothiazide (2) spironolactone with hydrochlorothiazide, (3) spironolactone alone, or (4) no diuretic (control; i.e., after diuretic). Hypercalciuria (urinary calcium greater than or equal to 0.15 mmol/kg/day) was observed in all but the control group. Covariate analysis demonstrated a significant effect of sodium, calcium, and vitamin D intakes (p less than 0.01) and sodium excretion (p less than 0.05) on urinary calcium excretion. Treatment with any of these diuretics in neonates may be associated with abnormal renal losses of calcium, sodium, chloride, and potassium. From a nutritional perspective, neonates requiring long-term diuretic therapy thereby require special consideration, including monitoring of mineral excretion and renal ultrasonography.

Birth Weight↗