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Diuretic-induced severe hyponatremia. Review and analysis of 129 reported patients.

Thiazides were responsible for severe diuretic-induced hyponatremia (serum sodium level < 115 mEq/L) in 94 percent of 129 cases reported in the literature between 1962 and 1990. The hyponatremia developed within 14 days in most of the patients receiving thiazides but in none of the patients who were treated with furosemide. Diuretic-induced hyponatremia was four times more common in women than in men. Advanced age was not associated with a higher tendency for hyponatremia. In the majority of the patients who received thiazides, excess antidiuretic hormone activity, hypokalemia, and excess water intake were accompanying findings which, singly or together, appeared to contribute to the development of hyponatremia. In 12 patients, mortality was directly related to hyponatremia. Rapid average correction of hyponatremia and a relatively high total correction (over 20 mEq/L) in the first 24 h were significantly associated with higher mortality or demyelinating syndrome. The presence of neurologic signs is an indication for active sodium replacement. The onset of thiazide-induced hyponatremia may in some cases occur within 1 day and therefore needs to be corrected rapidly, but within a total elevation of 20 mEq/L in the first 24 h. Where the onset is judged to have been slow (over several days), the level should be corrected at a slow rate, up to a total of 12 to 15 mEq/L in 24 h.

Adult↗

Bronchial hyperresponsiveness to inhaled methacholine in subjects with chronic left heart failure at a time of exacerbation and after increasing diuretic therapy.

Cough and wheezing are common findings in left heart failure. However, it is still questionable whether nonallergic bronchial hyperresponsiveness, the hallmark of asthma, is also associated with this condition. In 12 subjects with acute decompensation of chronic postischemic LV failure, we assessed the PC20 methacholine during an episode of acute LV failure and after five to 15 days of intensive diuretic therapy. Weight, arterial blood gases, plethysmographic lung volumes, and expiratory flows were also measured on both visits. Extravascular lung water was estimated indirectly with a radiologic score. During acute decompensation, six subjects had significant airway obstruction and eight had a PC20 less than or equal to 16 mg/ml (significant bronchial hyperresponsiveness). After diuretic therapy, subjects improved significantly, losing an average of 2.2 kg, but they still had chronic LV failure and evidence of an obstructive breathing defect. Although mean PC20 was unchanged, three subjects had significantly improved PC20 after treatment. We conclude that: (1) left ventricular failure is often associated with mild bronchial hyperresponsiveness, although it is not excluded that smoking and the resulting possibility of bronchial obstruction can also play some role; and (2) acute treatment does not generally alter bronchial responsiveness to methacholine, suggesting that chronic LV failure can cause chronic changes to the airways.

Aged↗

Insulin resistance induced by loop diuretics and hyperosmolarity in perfused rat liver.

Insulin-induced cell swelling was recently suggested to reflect an independent signal for metabolic insulin effects such as inhibition of hepatic proteolysis, which is transmitted at the level of autophagosome formation via p38MAPK activation [Häussinger et al., Gastroenterology 116 (1999), 921-935]. Here, the role of insulin-induced cell swelling in the overall context of insulin signalling towards proteolysis inhibition was studied in perfused rat liver. Loop diuretics and hyperosmolarity, which impair insulin-stimulated cell swelling, strongly blunt Erk-2 and p38MAPK activation as well as proteolysis inhibition by insulin, but are without effect on insulin-induced tyrosine phosphorylation of IR-beta and IRS-1. Inhibitors of phosphatidylinositol-3-kinase (PI3-kinase) also block insulin-induced cell swelling, MAP kinase activation and proteolysis inhibition, but the antiproteolytic response to hypoosmolarity remains unaffected. We suggest that PI3-kinase-mediated cell swelling induced by insulin is required to amplify the insulin signal to MAP kinases and thus proteolysis regulation. The perturbation of insulin-induced cell swelling may be of pathophysiological relevance for the development of insulin resistance in clinical situations associated with hyperosmotic dehydration and loop diuretic treatment.

Animals↗

Characterization of a diuretic peptide from Locusta migratoria.

A diuretic peptide Locusta-DP, identified by its ability to increase cyclic AMP production in locust Malpighian tubules in vitro, has been isolated and characterized from whole heads of Locusta migratoria. The purified peptide stimulates fluid secretion by Malpighian tubules maximally in vitro. The primary structure of Locusta-DP was established as a 46 residue amidated peptide: MGMGPSLSIVNPMDVLRQRLLLEIARRRLRDAEEQIKANKDFLQQI-NH2. Locusta-DP has 48% sequence identity with Acheta-DP and 49% identity with Manduca-DH, and provides further evidence for the presence of a family of diuretic peptides in insects.

Amino Acid Sequence↗

Electrocardiographic J wave as a result of hypercalcemia aggravated by thiazide diuretics in a case of primary hyperparathyroidism.

Electrocardiographically, the QT interval is shortened, ST segment is depressed, and T wave becomes negative in hypercalcemia. The use of diuretics in cases with hyperparathyroidism decreases the excretion of calcium, causes changes in bone-calcium turnover and parathyroid hormone activity, and forms hypercalcemia. A 67 year-old Turkish female patient in whom we electrocardiographically observed a J wave is presented as a hypercalcemic case with primary, hyperparathyroidism aggravated by the use of a thiazide diuretic.

Aged↗

Thiazide diuretics arrest the progression of nephrocalcinosis in children with X-linked hypophosphatemia.

OBJECTIVE: X-linked hypophosphatemia (XLH) is characterized clinically by rickets, hypophosphatemia, and hyperphosphaturia. Conventional treatment of XLH with oral phosphate and vitamin D is associated with increased urinary calcium excretion and nephrocalcinosis. Thiazide diuretics decrease urinary calcium excretion. The objective of this study was to determine the effect of thiazide diuretics on the clinical and radiologic course of nephrocalcinosis in children with XLH. METHODS: The effect of hydrochlorothiazide (HCTZ) on clinical and radiologic progression of nephrocalcinosis was evaluated in 11 children with XLH. All patients had been treated previously with vitamin D and oral phosphate and had radiologic evidence of nephrocalcinosis. The average age of the patients at the start of HCTZ was 6.6 +/- 1.0 years. The effect of oral HCTZ at 0.8 +/- 0.1 mg/kg body weight per day given for 3.3 +/- 0.6 years on the progression of nephrocalcinosis and urinary calcium excretion was evaluated. RESULTS: There was no change in serum phosphorous, calcium, potassium, and chloride after HCTZ therapy. HCTZ therapy increased serum bicarbonate and decreased urinary calcium excretion. The grade of nephrocalcinosis increased from 0.4 +/- 0.2 to 1.5 +/- 0.3 in the 2.3 +/- 0.3 years before initiation of HCTZ therapy, whereas the degree of nephrocalcinosis was stable after 3.3 +/- 0.6 years of HCTZ therapy (1.5 +/- 0.3 vs 3.0 +/- 0.3). CONCLUSION: HCTZ decreased urinary calcium excretion but did not result in the resolution of nephrocalcinosis. However, when compared with the control period, HCTZ prevented the progression of nephrocalcinosis in children with XLH.

Calcium↗

Thiamin, selenium, and copper levels in patients with idiopathic dilated cardiomyopathy taking diuretics.

OBJECTIVE: To analyze the association of thiamin, selenium, and copper serum levels with cardiac function in patients with idiopathic dilated cardiomyopathy using diuretics, and also to compare them with levels in control patients with no evidence of disease. METHODS: The study comprised 30 patients with heart disease and 30 healthy control individuals. Thiamin was analyzed by measuring the activity of erythrocytic transketolase and the effect of thiamin pyrophosphate. Selenium and copper serum levels were measured by hydride generation and flame atomic absorption spectrophotometry, respectively. RESULTS: Thiamin deficiency was observed in 10% of the control individuals and in 33% of the patients with heart disease (p=0.02). The mean selenium and copper serum levels in control individuals and patients with heart disease were, respectively, 73.2+/-9.9 microg/L (56.5 to 94.5 microg/L) and 72.3+/-14.3 microg/L (35.5 to 94 microg/L) (p=0.77); 1.1+/-0.4 mg/L (0.6 to 1.8 mg/L) and 1.2+/- 0.4 mg/L (0.6 to 2.2 mg/L) (p=0.27). No association between the levels of these nutrients and cardiac function was observed. CONCLUSION: Thiamin deficiency was significantly more frequent in patients with heart disease. No significant difference was observed between the mean selenium and copper serum levels in control individuals and in patients with heart disease. The results suggest possible benefits with thiamin replacement in patients taking diuretics.

Adult↗

Diuretic and enhanced sodium restriction results in improved antiproteinuric response to RAS blocking agents.

Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics may exert synergistic antiproteinuric effects. Eighteen patients with a proteinuria >1 g/24 h after 6 mo of treatment with ramipril at 5 mg/d were assigned to receive in random order ramipril at 10 mg/d, valsartan at 160 mg/d, or combined ramipril at 5 mg/d and valsartan at 80 mg/d in addition to their antihypertensive treatment. The treatment periods lasted 4 wk and were separated by a 4-wk washout with ramipril at 5 mg/d. At the end of this crossover sequence, patients received combined ramipril at 5 mg/d, valsartan at 80 mg/d, and an increased furosemide dosage for an additional 4-wk period. The primary end point was the urinary protein/creatinine ratio for two 24-h urine collections at the end of each treatment period. No significant differences were noted between the study end points of the ramipril 10, valsartan 160, and combined ramipril 5 and valsartan 80 treatment groups. However, the urinary protein/creatinine ratio was lower with combined ramipril 5 and valsartan 80-increased furosemide dosage than with valsartan 160 and combined ramipril 5 and valsartan 80, with a similar tendency compared with ramipril 10. Combined ramipril 5 and valsartan 80-increased furosemide dosage decreased systolic home BP and increased serum creatinine but did not significantly increase the number of symptomatic hypotension cases compared with the other three treatments. Thus, in patients with severe proteinuria and hypertension, a cautious increase in diuretic dosage in addition to combined angiotensin-converting enzyme inhibitors and angiotensin receptor blockers decreases proteinuria and BP but may expose the patient to prerenal failure.

Adult↗

Natriuretic and diuretic actions of a highly selective adenosine A1 receptor antagonist.

The natriuretic and diuretic action of a highly selective adenosine A1 receptor (A1AdoR) antagonist, 1,3-dipropyl-8-[2-(5,6-epoxy)norbornyl]xanthine (CVT-124), was investigated in anesthetized rats. CVT-124 (0.1 to 1 mg/kg) caused dose-dependent increases in urine flow and fractional and absolute sodium excretion of by six- to 10-fold and, at 0.1 mg/kg, increased the GFR (1.6+/-0.1 to 2.5+/-0.2 ml/min; P<0.01). There were no changes in BP or heart rate. CVT-124 reduced absolute proximal reabsorption (26+/-3 to 20+/-2 nl/min; P<0.05) despite unchanged proximally measured, single-nephron GFR (SNGFR) (42+/-5 to 44+/-4 nl/min; NS) and thereby decreased fractional proximal reabsorption (60+/-3 to 46+/-4%; P<0.05). Despite increasing distal tubular fluid flow rate (5.4+/-0.7 to 9.7+/-0.9 nl/min; P<0.001), it reduced the proximal-distal difference in SNGFR (before: 9.4+/-1.0 versus during CVT-124: 4.6+/-1.5 nl/min; P<0.01), suggesting that it had blunted the effects of the macula densa on SNGFR. Direct measurements of maximal tubuloglomerular feedback (TGF) responses were made from proximal stop flow pressure (PSF) during orthograde loop perfusion from the proximal tubule with artificial tubular fluid at 40 nl/min. TGF was blunted by intravenous CVT-124 (0.5 mg/kg; deltaPSF with vehicle: 8.3+/-0.6 versus CVT-124: 6.5+/-0.3 mm Hg; n = 9; P<0.01). In conclusion, A1AdoR blockade reduces proximal reabsorption and uncouples it from glomerular filtration. It increases distal delivery of fluid yet does not activate a macula densa-dependent fall in SNGFR because it blunts the TGF response. Natriuresis accompanied by blockade of proximal glomerulotubular balance and TGF characterizes a new class of diuretic drugs.

Analysis of Variance↗

Cellular actions of thiazide diuretics in the distal tubule.

Thiazide diuretics inhibit electroneutral NaCl reabsorption across the distal tubule of the salamander, Amphiuma, and hyperpolarize the basolateral membrane voltage (Vbl) of distal tubule cells. The objective of this study was to determine whether thiazides hyperpolarize Vbl by reducing intracellular Cl- activity (Acl). To this end, distal tubules were perfused in vitro, and electrophysiological techniques were used to measure Acl and Vbl. Hydrochlorothiazide in tubular fluid reduced ACl from 17.0 to 12.6 mM and hyperpolarized Vbl by 16 mV. Reduction of Cl- in tubular fluid from 84 to 8 mM also decreased Acl from 16.1 to 9.9 mM and hyperpolarized Vbl by 12 mV. Because a previous study suggested that electroneutral NaCl reabsorption is mediated by Na+/H(+)-Cl-/HCO3- exchangers in the apical membrane, the Cl-/HCO3- exchange inhibitor, 4,4-diisothiocyanostilbene-2-2-disulphonic acid (DIDS) was added to tubule fluid. DIDS reduced Acl from 15.0 to 11.6 and hyperpolarized Vbl by 10 mV. DIDS and hydrochlorothiazide were not additive, inhibition of Na+/H+ exchange by amiloride (10(-3) M) and Na+ replacement with N-methyl-D-glucamine also reduced Acl from 17.4 to 12.9 and hyperpolarized Vbl by 16 mV. The hyperpolarization of Vbl in each experiment is referable to the fall in Acl. These data show that thiazide diuretics regulate ACl and that the hyperpolarization of Vbl is referable to the thiazide-induced reduction of Acl.

Animals↗

Adrenocortical steroids increase renal thiazide diuretic receptor density and response.

The density of the rat renal pharmacologic receptor for thiazide-type diuretics, as quantitated by the maximal specific binding of (3H)metolazone, decreased to one-third normal after adrenalectomy. Selective glucocorticoid (dexamethasone or RU-28362) replacement increased thiazide receptor density to or above the normal level over the dose range of steroid that decreased thymus weight, which served as a bioassay for glucocorticoid activity. Mineralocorticoid (fludrocortisone or aldosterone), in doses that did not decrease thymus weight, also increased thiazide diuretic receptor density to or above normal. The addition of glucocorticoid (RU-28362) to maximal aldosterone increased thiazide receptor above that produced by aldosterone alone and to threefold normal. Similarly, the addition of aldosterone to high-dose RU-28362 also increased thiazide receptor density above that produced by the glucocorticoid alone and to threefold normal. Hence, the effects of glucocorticoids and mineralocorticoids appeared to be additive. The increase in renal thiazide receptor density produced by fludrocortisone, at a dose that elicited both mineralocorticoid and glucocorticoid effects, was unrelated to the basal (prethiazide) renal excretion of sodium, potassium, chloride, or calcium. However, fludrocortisone-pretreated animals responded to bendroflumethiazide with a greater natriuresis than did controls. In addition, the magnitudes of the thiazide-elicited natriuresis and chloriuresis correlated significantly with thiazide receptor. It was concluded that both the density of the renal thiazide receptor and the quantity of sodium and chloride reabsorbed by the thiazide-sensitive Na-Cl cotransporter in the kidney are under adrenocortical regulation.

Adrenalectomy↗

Felodipine in combination with a beta-blocker and a diuretic in chronic treatment of patients with refractory primary hypertension.

The acute antihypertensive effects of the dihydropyridine calcium antagonist, felodipine, were investigated in 12 male patients aged 43 to 64 years with uncontrolled blood pressure on combined treatment with a thiazide diuretic, a beta-blocker and hydralazine. Central and renal haemodynamics were monitored after acute oral administration (0.075 mg/kg) of felodipine in combination with the beta-blocker and diuretic. Six patients were continued on long term oral felodipine (mean dose 20 +/- 24 mg/day) in combination with the other drugs for 6 to 18 months. Ambulatory blood pressure was measured repeatedly and renal function re-examined once during long term felodipine therapy. In the 6 patients on long term therapy, systolic blood pressure was reduced from 190 +/- 17 to 149 +/- 24 mm Hg and diastolic blood pressure from 116 +/- 12 to 89 +/- 14mm Hg (p less than 0.001). No significant change in heart rate was observed (65 +/- 4 vs 62 +/- 10 beats/min). Renal plasma flow significantly increased from 284 +/- 97 to 425 +/- 131 ml/min/m2 (p less than 0.01) but glomerular filtration rate was unchanged (72 +/- 20 vs 80 +/- 22 ml/min/m2). Hence, the filtration fraction was significantly reduced and normalised in all patients (0.26 +/- 0.04 vs 0.20 +/- 0.03) [p less than 0.05]. Bodyweight was unchanged. It is concluded that felodipine is a highly potent vasodilator with a favourable effect on renal function and is suitable for long term therapy in patients with severe primary hypertension.

Adrenergic beta-Antagonists↗

Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium.

The effect of thiazide diuretics on the glucose tolerance of seven normal men in whom potassium loss was prevented with supplementation was studied using the glucose clamp technique. An initial control 2-h hyperglycemic clamp was performed to create a square wave of hyperglycemia 125 mg/dl above basal. At 1 h, 40 g glucose/m2 body surface area was ingested. Serial insulin (IRI) and gastric inhibitory polypeptide (GIP) levels were measured as well as the level of glucose infusion necessary to maintain the stable hyperglycemic level. After the initial study, subjects were placed on a 10-day course of 100 mg hydrochlorothiazide and 80 meq potassium per day. Subjects were monitored for dietary potassium intake, urinary potassium, and sodium losses, and the replacement of potassium adjusted accordingly. A repeat glucose clamp was done on day 10. When potassium losses were prevented, thiazides induced no alterations in glucose tolerance, beta-cell sensitivity to glucose, GIP-cell sensitivity to glucose, beta-cell sensitivity to GIP, or tissue sensitivity to insulin. Two control studies in which hypokalemia was allowed to ensue after hydrochlorothiazide ingestion revealed a diminution in glucose tolerance, a consequence of diminished pancreatic beta-cell response to glucose. We conclude that the thiazide effect on glucose tolerance is a consequence of the resultant hypokalemia that the diuretic may create.

Adolescent↗

Effectiveness of continuous infusions of loop diuretics for severe heart failure.

Heart failure is a growing worldwide epidemic resulting in frequent hospitalizations and increased resource utilization. A major cause of hospitalization is congestive symptoms and impaired functional capacity due to sodium and water retention. Diuretic resistance, which is common among patients with severe heart failure, may inhibit diuresis, thus prolonging hospitalizations. The current evidence suggests that continuous infusions are a potentially effective method for delivering high daily doses of diuretics and rapidly removing large amounts of excess sodium and water. In our experience, continuous intravenous infusions of furosemide are well tolerated and may shorten hospitalizations, which in turn reduces overall costs. Although the current evidence is largely limited to observational reports and small uncontrolled studies, the consistent findings of efficacy and safety warrant the further investigation of this treatment strategy in randomized controlled trials.

Diuretics↗

A survey of the effects of loop diuretics on the zonulae occludentes of the perilymph-endolymph barrier by freeze fracture.

The acute (30 min) effects of the loop diuretics piretanide, ethacrynic acid, bumetanide, furosemide, and azosemide, and the chronic (8 days) effects of furosemide and bumetanide on the zonulae occludentes (tight junctions) of the perilymph-endolymph barrier in the stria vascularis and in Reissner's membrane of the basal cochlear turns were studied by freeze-fracture. Quantitative analysis of their effects indicated that the structural integrity of the barrier was modified by either as increase or a decrease in the number, depth, and density of the strands of the tight junctions of the strial marginal cells. Only azosemide appeared to modify the tight junctions between the epithelial cells of Reissner's membrane, but it had little effect on the strial junctions. The tight junctions between the basal cells of the stria appeared to be the least affected by the various loop diuretics, although piretanide appeared to increase randomly the intercellular spaces lying between the strands.

Animals↗

Beta-blockers, diuretics and physical fitness as determinants of serum lipids in myocardial infarction patients.

Serum lipid levels were followed in myocardial infarction patients for one year after the infarction and related to their drug use and physical performance. Serum triglyceride concentrations were significantly elevated in patients using diuretics or diuretics and beta-blockers together both 3 and 12 months after the infarction when compared to patients not having drugs. The beta-blockers alone did not change triglycerides. No differences were found in total cholesterol concentration between any of the drug groups. The HDL cholesterol levels were significantly lower in all the drug groups 12 months after the infarction in comparison with the group using no drugs, but 3 months after the infarction these differences were not present. Total work in the exercise stress test correlated negatively with serum triglycerides and total cholesterol and positively with HDL/total cholesterol ratio in the group using no drugs 12 months after the infarction. In beta-blocker users, total work correlated negatively with triglyceride and total cholesterol concentrations. In all drug groups no correlation between total work and HDL/total cholesterol ratio could be found. These data suggest that despite differences in the physical working capacity between the groups, the drugs themselves are major determinants of differences in serum lipids.

Adrenergic beta-Antagonists↗

Chronic effects of loop diuretics on the guinea-pig cochlea.

Groups of pigmented guinea pigs (weighing 480 to 650 g at the start of the experiment) were given daily intraperitoneal injections of 16 mg/kg bumetanide or 10, 20 or 40 mg/kg furosemide over a period of 4 weeks. Two weeks following the last diuretic dose the animals were anaesthetized with urethane and the responses of single auditory nerve fibres to pure-tone and click stimuli were recorded. The tuning of individual units, as measured by Q10 dB values of frequency threshold curves, tended to be more affected than threshold at characteristic frequency by both loop diuretics. Light microscope examination of treated cochleas suggested greater effect of the drugs on the organ of Corti than on stria vascularis.

Animals↗

Osmotic diuretics and hemodilution in postischemic renal failure.

In the acute phase of ischemic renal failure, the severe depression of the glomerular filtration rate (GFR) is due to obstruction of the tubules by cells and cell debris rejected from the proximal tubules, a blockade which can be prevented at least partly, by treatment with osmotic diuretics. The isosthenuria, the second typical sign in ischemic acute renal failure, probably derives from the medullary ischemia that results from an intracapillary trapping of red cells. This, in turn, is suggested to be caused by oxygen-derived free radicals, which via increasing the capillary macromolecular permeability result in a massive extravasation of plasma and hence in hemoconcentration. As expected from this hypothesis, scavengers may ameliorate both the trapping and the consequent medullary ischemia. Unfortunately, however, a therapy using both osmotic diuretics and scavengers fails to improve the long-term outcome. Hemodilution would seem more promising, since it will both prevent the medullary ischemia seen in the acute phase and substantially improve the long-term outcome. At a hematocrit of 0.30, rat kidneys exposed to 45-min ischemia will show a GFR 1 month after the insult of more than 50% of the normal GFR as against 15% in untreated animals.

Acute Kidney Injury↗