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PubMed1980

cAMP-stimulated cation cotransport in avian erythrocytes: inhibition by "loop" diuretics.

The effect of a series of diuretically active substituted 3-aminobenzoic acid derivatives and related compounds was investigated on a cyclic AMP-activated Na+-K+ cotransport system in avian erythrocytes. A good correlation between the diuretic potency of this class of "loop" diuretics in the dog and their inhibition of cation cotransport in turkey erythrocytes was found. Selected thiazide-type diuretics were found to be ineffective. The most active compound tested (3-benzylamino-4-phenylthio-5-sulfamoylbenzoic acid) had an effective dose50 of 4.6 x 10(-8) M in the avian system, and was about 5 times more potent than bumetanide and 500 times more potent than furosemide in this regard. The diuretics appear to interact directly with the cation transport system itself, and not with some antecedent step in the sequence of events from intracellular cAMP accumulation to stimulation of transport. The compounds tested did not appear to compete at Na+- or K+-binding sites on the transport system. The similarity in the structure-activity relationship of these agents in the avian erythrocyte and the kidney suggests that the avian erythrocyte may be a useful model for analysis both of the diuretic-sensitive transport system of the mammalian kidney, and of the molecular mechanism of loop diuretic action.

Aminobenzoates↗
PubMed1990

Loop diuretic and anion modification of NEM-induced K transport in human red blood cells.

The thioalkylating agent N-ethylmaleimide (NEM) causes ouabain-insensitive K loss from human red blood cells. This K loss is inhibited when intracellular Cl is replaced by another permeant anion or when loop diuretics are placed in the incubation medium after NEM exposure. In this report, we have tested the possibility that Cl replacement or loop diuretics not only influence the transport of K induced by NEM but also the interaction of NEM with its target sulfhydryl group. This possibility was examined by replacing intracellular Cl or exposing the cells to loop diuretics before NEM exposure, then measuring K loss in a Cl medium free of loop diuretics. We found that such pretreatment with either Cl substitution or loop diuretics stimulated, rather than inhibited, NEM-induced K loss. This enhancement was not additive in that the increase in K loss induced by anion substitution was not increased further when loop diuretics were also present. These data suggest that anion substitution and loop diuretics enhance the interaction of NEM with its cellular target but inhibit the K loss induced by NEM.

Anions↗
PubMed1993

Immunocytochemical characterization of the high-affinity thiazide diuretic receptor in rabbit renal cortex.

Thiazide diuretics increase urinary NaCl excretion primarily by inhibiting Na and Cl transport across the apical membrane of cells in the renal distal tubule. Although these diuretics bind to a membrane protein that couples transport of Na and Cl directly, the molecular nature of this transporter and its localization in the mammalian kidney remain controversial. The present experiments were designed to develop monoclonal antibodies to the high-affinity thiazide diuretic receptor to investigate its molecular characteristics and its cellular and subcellular localization in rabbit kidney. Mice were immunized with high-affinity thiazide diuretic receptors that had been partially purified from rabbit kidney cortex. Resulting hybridomas were screened for the ability to immunoprecipitate thiazide diuretic receptors that were labeled with the thiazide-like diuretic [3H]metolazone. A single hybridoma (MAb JM5) produced antibodies capable of immunoprecipitating up to 80% of the labeled thiazide receptors from solubilized renal cortical membranes. MAb JM5 reacted with a 125-kDa protein on Western blots of solubilized renal cortical apical membranes. It stained the apical membrane of cells in the distal convoluted and connecting tubule but did not stain proximal tubules, glomeruli, or interstitial structures. Less intense staining of apical membranes of principal cells in the collecting tubule and a subpopulation of cells in the thick ascending limb were also present. These results indicate that the high-affinity thiazide diuretic receptor comprises a 125-kDa protein that localizes to the apical membrane of cells in the renal distal tubule.

Animals↗
PubMed1994

Haemodynamic impact of diuretic therapy in chronic heart failure.

An immediate improvement in haemodynamic variables and cardiac performance is achieved in chronic heart failure following diuretic therapy, primarily due to reductions in plasma and extracellular fluid volumes. Humoral markers of these alterations are increased plasma renin, angiotensin and aldosterone levels; these increase maximally over the first week of treatment but attenuate during sustained therapy. There are reciprocal alterations in plasma alpha-atrial natriuretic peptide levels. These findings suggest that the initial volume contraction is maintained, though somewhat attenuated, during chronic therapy. The neurohumoral consequences of diuretic therapy are of particular interest in heart failure, as they may contribute to diuretic resistance. Activation of the renin-angiotensin system favours the proximal tubular reabsorption of sodium and water, which may result in dilutional hyponatraemia. Diuretics have both direct vascular and non-vascular (volume-dependent) haemodynamic actions. Together these substantially reduce the left heart filling pressure (-29%) with a consequent fall in cardiac output (-10%). Systemic vascular resistance initially increases but subsequently normalizes, allowing cardiac output to return towards control values. Haemodynamic tolerance to diuretics does not usually occur during sustained oral therapy; additionally, echocardiographic contractility indices and exercise capacity may increase. The vasodilator activity of the diuretics is due to prostaglandin release; the initial pressor action is due to activation of the renin-angiotensin system. Direct pulmonary vasodilatation with improved pulmonary compliance remains an interesting possibility. Over the longer term, substantial reductions in left heart filling pressure during exercise occur at unaltered cardiac output. The impact of diuretic therapy on the underlying myocardial disease process is unknown.(ABSTRACT TRUNCATED AT 250 WORDS)

Diuretics↗
PubMed1990

Role of macula densa in diuretics-induced renin release.

Diuretic therapy may enhance renin release by various mechanisms, principally contraction of extracellular fluid volume and its effects, including a fall in arterial pressure. Awake hydropenic or volume-expanded rats received diuretics (amiloride and hydrochlorothiazide) that are known inhibitors of NaCl transport beyond the macula densa; also the well-known Na(+)-K(+)-2 Cl- transport system inhibitor furosemide was administered. We also evaluated the effect of a dose of ethacrynic acid (a drug that shares the same mechanism of action as furosemide but is not diuretic in the rat). The direct action of the diuretics on renin-producing cells was examined in isolated glomeruli; a rise in renin release was observed with the calmodulin inhibitor trifluoperazine (10(-5) M). Renin release in intact hydropenic rats was not altered by diuretic therapy, but furosemide increased plasma renin activity in hydropenic as well as in volume-expanded rats. This demonstrates the importance of furosemide inhibition of transport in the macula densa for its renin secretory action. None of the diuretics (amiloride, hydrochlorothiazide, ethacrynic acid, or furosemide) elicited changes in renin release from glomeruli (10(-6) to 10(-3) M); amiloride and hydrochlorothiazide (10(-4) to 10(-3) M) did not change renin release from slices, but 10(-3) M ethacrynic acid and furosemide increased renin secretion in this preparation. This suggests that an effect on the macula densa is essential in loop diuretic-mediated renin release.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Failure of the loop diuretic torasemide to improve renal function of hypoxemic vasomotor nephropathy in the newborn rabbit.

The use of diuretic therapy in vasomotor nephropathy is a controversial topic. It is generally agreed that diuretics in this situation enhance urinary output, reduce the degree of volume expansion, and improve cardiac and especially the compromised lung function. It is less clear whether diuretic therapy improves kidney function. The present study evaluates the effects of intravenous torasemide on renal function in 25 anesthetized ventilated hypoxemic newborn New Zealand White rabbits with vasomotor nephropathy. This well-established animal model mimics the renal physiology of the human newborn and, in particular, that of the premature infant. Three groups of hypoxemic rabbits were studied. The animals of group 1 (n = 8) received no diuretic therapy (hypoxemic control), and those of group 2 (n = 9) were given a single intravenous dose of torasemide (1 mg/kg) in a curative fashion 2 h after hypoxemia was induced. In the third group of animals (n = 8), torasemide was given preventively; a bolus intravenous dose of torasemide (0.2 mg/kg) was given before the induction of hypoxemia and sustained by the addition of 0.2 mg x kg(-1) x h(-1) of the drug to the continuous intravenous infusion given throughout the entire 3-h hypoxemic period. Hypoxemia alone (group 1) caused acute renal insufficiency with a significant fall in mean arterial blood pressure, GFR, and renal blood flow; the renal vascular resistance increased, and the filtration fraction was unchanged. The curative dose of torasemide (group 2) induced a significant diuresis and natriuresis with minimal augmentation of urinary potassium excretion, converting mildly oliguric to nonoliguric acute renal insufficiency. In this group of animals, torasemide did not improve the glomerular dysfunction. The preventive dose of torasemide (group 3) even somewhat worsened the already impaired renal functions without further increasing the diuretic effect of the drug. We conclude that in hypoxemic newborn animals with renal dysfunction, torasemide is an effective potassium-sparing diuretic that unfortunately does not improve renal blood flow and GFR. The failure of torasemide to attenuate the glomerular dysfunction of hypoxemic vasomotor nephropathy in the newborn rabbit is disturbing. These data certainly caution against the overzealous use of loop diuretics in hypoxemic oliguric neonates.

Acute Kidney Injury↗
PubMed1987

A new uricosuric diuretic, S-8666, in rats and chimpanzees.

5-Dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxyli c acid (S-8666) was studied as a possible new uricosuric diuretic agent using rats and chimpanzees. Various new compounds belonging to the 5-sulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acids were clearly diuretic with uricosuric activity in intraperitoneally oxonate-treated rats. S-8666 was chosen as a favorable candidate because its uricosuric activity due to the effects of tubular transport of uric acid were apparently more marked than those of known uricosuric agents such as probenecid, benzbromarone, tienilic acid and indacrinone in oxonate-treated rats. S-8666 was also uricosuric in rats not given urate oxidase inhibitor. The diuretic effect of S-8666 in oxonate-treated rats was as high-ceilinged as that of furosemide, while those of tienilic acid, indacrinone and a known compound of a 5-carbonyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid were rather low-ceilinged. These uricosuric and diuretic activities of S-8666 were manifested by two enantiomers, of which the (+)-enantiomer displayed predominantly uricosuric activity and the (-)-enantiomer, diuretic activity like furosemide. The new compound was also uricosuric and diuretic in chimpanzees, although the potency of the uricosuric activity was similar to that of probenecid and less than that of indacrinone. Thus, it seems that S-8666 is a different type of uricosuric diuretic from known agents which have already been tried in humans.

Animals↗
PubMed1986

The effects of antihypertensive drugs on serum lipids and lipoproteins, I. Diuretics.

Potassium-losing diuretic drugs, when used in the treatment of hypertension, cause unfavourable short term alterations in blood lipid and lipoprotein concentrations. The disturbance is characterised by increases in total cholesterol of 4 to 13%, in low density lipoprotein (LDL) cholesterol of 7 to 29%, in very-low density lipoprotein (VLDL) cholesterol of 7 to 56%, and in total triglyceride of 14 to 37%. The disturbance is variable among patients and over time in individual patients; it is absent in some. In long term treatment the data are fragmentary, but total cholesterol and triglycerides usually return to baseline values or below. The variability of the lipid response to diuretics has several consequences: firstly, it necessitates a sizeable study population (minimum of 30 patients) in order to document convincingly its presence or absence; secondly, lipoprotein fractions must be examined to define the pattern of the disturbance; and thirdly, the subsidence of the diuretic-induced lipid effects in long term treatment may be more apparent than real because even larger decreases have been noted in untreated groups in the few studies that wisely included these important controls for comparison. While the cause of the lipid-lipoprotein aberration is unclear, existing data suggest that certain attributes of the study population influence the response, i.e. age, habitual diet, hormonal milieu (gender), baseline cholesterol concentrations, and induced glucose intolerance. The apparent absence of lipid alterations with indapamide needs to be substantiated and compared with low doses of a standard thiazide-type drug. The lipid-lipoprotein effects of diuretics seem inconsequentially small, but they may contribute to the disappointing failure of diuretic-based regimens to lower the incidence of coronary heart disease in hypertensive patients. Nevertheless, diuretic-based treatment remains the only therapeutic regimen of proven benefit to congestive heart failure in patients with hypertension, and it is superior to beta-blockade in preventing stroke. Hence, alternative antihypertensive drug regimens must be compared prospectively with diuretics in order to verify any theoretic superiority.

Antihypertensive Agents↗
PubMed1997

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.

Adolescent↗
PubMed2000

Diuretic renography with the addition of quantitative gravity-assisted drainage in infants and children.

UNLABELLED: The aim of this study was to evaluate the use of quantitative gravity-assisted drainage (GAD) using >50% residual activity as an indicator to confirm obstruction in diuretic renography in the investigation of hydronephrosis and hydroureteronephrosis in infants and children. This was evaluated in 2 groups: furosemide clearance half-time (t 1/2) > 20 min (obstructed range) and t 1/2 = 10-20 min (indeterminate range). METHODS: Two hundred children (155 boys, 45 girls; age range, 2 d to 16 y; median age, 26 wk) were studied over a 2-y period. One hundred thirty-five F+20 (diuretic given 20 min after radiopharmaceutical) and 65 F+0 (simultaneous administration of diuretic and radiopharmaceutical) studies were performed with intravenous administration of 99mTc-mercaptoacetyltriglycine (MAG3) and furosemide. At the end of the 20-min diuretic phase, a 5-min post-GAD image was obtained, and the percentage of residual activity was calculated by comparison with the last 5 min of the diuretic phase. All patients were monitored for 6-12 mo, and the final diagnoses were based on either surgical findings or conservative management with follow-up sonography or 99mTc-MAG3 studies. Results of the diuretic renography using quantitative GAD were then compared with the final diagnoses. RESULTS: A renal unit was defined as a kidney and its ureter. In the 200 patients studied, 256 hydronephrotic renal units were analyzed: 10 units showed no function, 1 unit showed poor function, 131 units had t 1/2 < 10 min, 62 units had t 1/2 > 20 min, and 52 units had t 1/2 = 10-20 min. Of the 131 renal units with t 1/2 < 10 min, there was only 1 case of obstruction. Using GAD > 50% residual activity for the diagnosis of obstruction in 62 renal units with t 1/2 > 20 min, the sensitivity was 88.4%, the specificity was 73.7%, and the accuracy was 83.9%. Similarly, using GAD > 50% residual activity for the diagnosis of obstruction in 52 units with t 1/2 = 10-20 min, the sensitivity was 100%, the specificity was 79.5%, and the accuracy was 82.7%. CONCLUSION: The quantitation of GAD > 50% residual activity in diuretic renography can help to differentiate between obstruction and nonobstruction in renal units with t 1/2 > 20 min and t 1/2 = 10-20 min. The quantitation of GAD when t 1/2 < 10 min is not useful because obstruction has already been excluded.

Adolescent↗
PubMed1992

[Loop-diuretics anno 1992. Mechanisms of effect and current therapeutic principles].

Loop-diuretics inhibit the Na+/K+/2Cl(-) -cotransport system in the thick ascending loop of Henle, and are the most potent of the diuretic agents. They also increase production of prostaglandins and, when given intravenously, reduce pulmonary capillary pressure. The clinical effects, and side effects, of loop diuretics are reviewed. In Norway, use of thiazide diuretics has declined, but use of loop-diuretics has remained unchanged. Loop-diuretics are still first-line drugs in cases of heart failure. The author discusses treatment of patients resistant to conventional doses of diuretics, and the causes of the resistance. Since furosemide and bumetanide may have very different effects and side effects, both are needed as treatment alternatives.

Bumetanide↗
PubMed1991

The impact of diuretic therapy on reported sexual function.

BACKGROUND: --Thiazide diuretics are the most commonly prescribed antihypertensive agent in the treatment of hypertension. No studies to date have isolated conclusively the effect of diuretic therapy on patient quality of life, and particularly on sexual dysfunction. METHODS: --We carried out a randomized placebo-controlled trial of the effect of thiazide diuretics on quality of life in mildly hypertensive men between the ages of 35 and 70 years. After a 1-month washout period off diuretic therapy, the men were randomized to a 2-month trial of a thiazide treatment or placebo. At the end of the trial, 176 men completed a confidential self-administered questionnaire assessing aspects of social performance, general well-being, and emotional and physiologic states. RESULTS: --Patients taking diuretics reported significantly greater sexual dysfunction than control subjects, including decreased libido, difficulty in gaining and maintaining an erection, and difficulty with ejaculation. Multivariate analysis suggested that the findings were not mediated by low serum potassium levels or by low blood pressure. Sexual dysfunction was noted more often in the confidential self-report questionnaire than in response to direct questions from clinicians. We found no differences between diuretic and placebo groups in measures of mood, general sense of well-being, ability to work, alertness, and social/recreational activities. CONCLUSIONS: --Thiazide diuretic use is associated with male sexual dysfunction but does not appear to adversely affect other aspects of quality of life.

Adult↗
PubMed1988

Age-related effects of diuretics in hypertensive subjects.

Although the literature on diuretic therapy for essential hypertension is abundant, little attention has been directed to age-related responses, and dose-response information in young compared to elderly patients is lacking. The pharmacokinetic characteristics of some diuretics are modified in the elderly, and these appear to be accounted for by an age-related decline in renal function. Whereas some studies have suggested that the antihypertensive effect of diuretics is enhanced in the elderly, the few "satisfactory" trials available have not confirmed earlier observations. Contrary to first impressions, symptomatic side effects with diuretics are not more frequent in older patients and some trials suggest they are less frequent than in younger hypertensive subjects. Of the biochemical changes induced by diuretics, azotemia, hyponatremia and perhaps hypokalemia appear more frequently in the elderly. The elderly, especially those with underlying cardiac disease, may be more susceptible to the arrhythmogenic effect of diuretics than healthy younger patients, but the evidence is suggestive rather than definitive. It was concluded from this survey of the literature that our knowledge of the age-related effects of diuretics in the treatment of essential hypertension is fragmentary and far from complete.

Aged↗
PubMed1986

Acute titration and chronic follow-up with captopril in hypertension. A one-year safety profile on combination therapy with captopril and a diuretic.

The present study examines acute titration with captopril and chronic follow-up data on captopril and a diuretic in patients with all forms of hypertension. Captopril was initiated in those patients in whom previous antihypertensive agents either failed to control high blood pressure or produced adverse reactions. Acute titration was done in 88 patients in whom average diastolic blood pressure was equal to or more than 95 mm Hg. Initial titration dosage was decided on the basis of initial blood pressure recordings. During initial titration, 5 patients received 12.5 mg, 51 received 25 mg, 28 received 50 mg, and the remaining 4 received 100 mg of captopril. Post-captopril blood pressure data were normalized by using pre-captopril data as 100% for each patient. The blood pressure-lowering effect of captopril on both systolic and diastolic blood pressure in all 88 patients was statistically significant (p less than 0.05), within forty-five minutes of captopril administration irrespective of the doses. No adverse reactions were seen during the acute titration. After the initial titration, in all 88 patients a diuretic was added to obtain a synergistic effect. Eleven patients were dropped from the study, for they could not follow the requirements of the protocol. In 77 patients the data for a one-year safety profile with captopril and diuretic were available. There were no overall significant statistical changes in serial white blood cell count, serum potassium, and serum creatinine values in those 77 patients. In 31 patients the initial and maintenance dosage of captopril and the diuretic remained unaltered for one year. Post-captopril blood pressure and heart rate data were normalized, pre-captopril data being considered as 100% in those 31 patients. The blood pressure data following captopril and a diuretic therapy compared with the pre-captopril data were statistically significant (p less than 0.05) throughout the study period. However, no significant changes in heart rates were observed during the study period. In all other patients, diuretic therapy was continued throughout the study period. In 6 severely hypertensive patients, an additional beta-blocker was needed for further control of high blood pressure. In 3 severe hypertensives with renal failure, besides a diuretic and a beta-blocker, minoxidil was needed to normalize their high blood pressure. In 4 of 77 patients, verapamil was used for treatment of either vasospastic angina or paroxsysmal supraventricular arrhythmia.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic beta-Antagonists↗
PubMed1987

Diuretics in the management of hypertension.

Thiazide diuretics have been in use for over 30 years in the treatment of hypertension. Their action results in a reduction in peripheral resistance without a significant decrease in cardiac output or a major shift in plasma volume. They are as or more effective than any of the other antihypertensive agents when used as monotherapy and can serve as baseline therapy in combination with any of the available adrenergic, converting enzyme-inhibiting agents, or calcium-entry blockers. There is a high degree of patient acceptance; titration to an effective dosage is relatively easy; and cost, relatively low. Although certain undesirable metabolic changes may occur following the use of these agents, most of them are controllable, and there is no evidence to date that they offset the benefits achieved by blood pressure lowering. Asymptomatic elevated uric acids have not been shown to be of great significance. If gout occurs, it can be managed. Alterations in glucose metabolism may occur, and in some patients, it appears that blood glucose levels are elevated over time. This is not a desirable metabolic change, but is one of doubtful prognostic significance. Changes in lipids are generally short-term, and in the major clinical trials, lipid levels have not remained elevated with a continuation of diuretic therapy. Although diuretics produce hypokalemia in a fairly high percentage of patients, this is not generally severe (less than 3.3 mEq per liter) and usually does not produce symptoms. There is no firm evidence that the hypokalemia produced by diuretics predisposes the patient to severe arrhythmias or sudden death, although this point has been emphasized repeatedly in recent publications. Diuretics can usually be given without potassium-maintenance therapy. However, hypokalemia should be prevented in the elderly, in patients with ischemic heart disease, left ventricular hypertrophy and those on digitalis, or with diabetes. We prefer potassium-sparing agents along with a diuretic over supplements to prevent hypokalemia; the number of pills is kept at a reasonable level, and cost is minimized. Physicians should continue to prescribe diuretics as first-step therapy in the majority of patients to maximize therapeutic outcome.

Blood Pressure↗
PubMed1978

1,4-Dimorpholino-7-phenylpyrido[3,4-d]pyridazine (SD-511) as a new type of diuretic agent.

Diuretic features of 1,4-dimorpholino-7-phenylpyrido[3,4-d]pyridazine (DS-511) were studied in rats and mice. DS-511 was similar in diuretic effect to that of hydrochlorothiazide (HC) in both species, but was more water diuretic and less potassium-releasing than HC. After oral administration of DS-511 to rats the diuretic effect promptly appeared and lasted for 4 to 5 h. These patterns on onset and duration were similar to those of furosemide and acetazolamide (AZ). DS-511 was effective in experimentally induced acidotic and alkalotic rats. When DS-511 was used in combinations with other diuretics such as HC, AZ and triamterene at their maximum effective doses, urine volume and sodium excretion further increased, but potassium did not. Diuretic activity of DS-511 was not reduced by daily oral administration for 10 days to rats. In rats DS-511 reversed antidiuretic hormone (ADH)-induced antidiuresis. These findings suggest that DS-511 differs in mode and/or site of action from the known diuretics.

Acidosis↗
PubMed1983

Determinants of access of diuretics to their site of action.

For consideration of the determinants of access of diuretics to their site of action to be meaningful, one must understand molecular modes of action of diuretics and the anatomic site of effect along the nephron in addition to determinants of the renal handling of diuretics. Although the molecular mode of action is known for a number of drugs, such as the inhibition of carbonic anhydrase by acetazolamide, that for loop diuretics remains obscure. Sites of diuretic action along the nephron have been well delineated through collation of results from in vitro and in vivo techniques in a variety of species. Loop diuretics clearly block chloride reabsorption throughout the thick ascending limb of the loop of Henle. Access of diuretics to their renal tubular sites of action varies among drugs. Important determinants are plasma protein binding, active tubular secretion, nonionic diffusion, and intrarenal metabolism.

Animals↗
PubMed1995

[Diuretics in the neonatal period].

Careful management of fluid and electrolytes may require the rational use of diuretic agents in some neonatal pathological conditions. High efficacy diuretics include "loop" diuretics--furosemide, bumetanide and ethacrynic acid. The elimination half-life and renal effects of furosemide are prolonged in newborn infants as compared with adults. In congestive heart failure, the mean net losses associated with a 1 mg i.v. dose of furosemide, are 28 ml/kg, 3.6 mmol/kg and 0.3 mmol/kg respectively for water, sodium and potassium. The furosemide--dopamine (2 micrograms/kg/min) combination may improve renal insufficiency in the course of respiratory distress syndrome (RDS). Furosemide also decreases the deleterious renal effects of indomethacin. Beneficial effect of furosemide has not been clearly demonstrated in RDS and bronchopulmonary dysplasia (BPD). Metabolic alkalosis, hypokalemia, renal calcifications, cholelithiasis and worsening in BPD outcome have been related to long-term administrations of furosemide. The risk of furosemide induced-ototoxicity has not been clearly assessed in newborn infants. Medium efficacy diuretics (thiazides) act primarily in the early distal tubule. Chlorothiazide may reduce calcium urinary excretion in neonates receiving long-term furosemide therapy. Weak diuretics (potassium-sparing diuretics and carbonic anhydrase inhibitors) cause excretion of less than 5% of the filtered sodium. Potassium-sparing diuretics are usually reserved for neonates with congestive heart failure and are always used in combination.

Benzothiadiazines↗