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In pursuing earlier studies, the synthesis of a series of 1 and 1,3- substituted 2-(4-chloro-3-sulfamoylbenzamido)isoindolines (V a-e), related to indapamide, is described. These compounds were evaluated for diuretic and antihypertensive activities.
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In sodium depleted rats, urine extracts of hydrated healthy human volunteers cause a significant increase in water and sodium excretion. Single injection of 100 micrograms/kg bw. of the urine extracts as well as infusion of approximately 100 micrograms/h over several hours induce diuresis and to a lesser degree natriuresis. The sodium and plasma albumin concentrations show similar changes in kidney tissue: in the exterior medulla, the concentrations of sodium and albumin decrease by only 10 and 9%, respectively, whereas in the interior medulla they are decreased by 22 and 23%, respectively. The values obtained for the interior medullary zones are statistically significant. The data show that there is an inhibitory effect of the urine extracts on sodium absorption in the renal medulla. It is assumed that the modulation of sodium excretion occurs in the inner medullary areas.
The effect of a single oral dose of 40 mg xipamide on urinary excretion of Na+, K+, Cl-, Ca2+ and Mg2+ in healthy subjects and in patients with varying degrees of renal impairment was compared with various conventional diuretics. Xipamide caused marked excretion of Na+ and Cl-, whereas the diuretic produced only moderate kaliuresis; urinary excretion of Ca2+ was increased in proportion to Na+, like the loop diuretics. Xipamide affected electrolyte excretion even in patients with a creatinine clearance below 30 ml/min, as do the loop diuretics, too. Therefore, the pharmacodynamic characteristics of xipamide are more like those of a loop diuretic than of a thiazide. Xipamide was good bioavailable, its t 1/2 beta was 7 h and urinary recovery of the undegraded drug was 40% of the given dose. In renal insufficiency, t 1/2 beta increased from 7 to only 9h, yielding a moderate increase in the AUC. Urinary recovery of the drug was reduced in proportion to the reduction in the creatinine clearance of the patient. Therefore, significant extrarenal elimination of the diuretic must be postulated, which suffices to prevent significant drug accumulation in renal failure.
1. The mechanism underlying the antidiuretic effect of thiazide diuretics in diabetes insipidus (DI) is unknown. This study addressed two specific questions: is the reduction in urine flow rate (V) related to a decrease in the delivery of fluid from the pars recta of the proximal tubules ('distal delivery'), and are there any changes in the expression and/or intracellular distribution of vasopressin stimulated water channels (AQP2) in the collecting ducts, during chronic thiazide-induced antidiuresis? 2. Nine Brattleboro rats with vasopressin-deficient DI were treated for 5 days with bendroflumethiazide (BFTZ), 9 mg kg(-1) day(-1) orally, and 9 Brattleboro rats were left untreated. BFTZ-treated DI rats showed a fall in V from approximately 200 to approximately 75 ml day(-1) and an increase in urine osmolality from approximately 130 to approximately 400 mosmol kg(-1). 3. BFTZ-induced antidiuresis was associated with a persistent loss of sodium, but not of potassium. After 5 days of treatment, clearance studies in conscious rats showed a tendency towards decreases in effective renal plasma flow (-7%), GFR (-12%) and lithium clearance (C(Li); used as marker for distal delivery) (-25%), compared with untreated controls, but none of these changes were statistically significant. There was no apparent relationship between C(Li) and V in BFTZ-treated or untreated DI rats. 4. BFTZ treatment did not change the expression of AQP2 in homogenates of cortex, outer or inner medulla from DI rats, or from normal Long Evans rats. Light and electron microscopic immunocytochemistry revealed no changes in intracellular distribution of AQP2 in principal cells from inner medullary collecting ducts of BFTZ-treated DI rats. 5. We concluded, (i) that although the antidiuretic effect of BFTZ in rats with DI is associated with a net loss of Na, the decrease in V shows no association with changes in distal delivery, as estimated by C(Li). (ii) Antidiuretic treatment with BFTZ does not alter the expression of subcellular distribution of AQP2 water channels in the collecting ducts. The mechanism underlying the chronic antidiuresis caused by thiazide diuretics in DI remains elusive.
Thiazide-type diuretics have enjoyed a considerable success in the management of hypertension. These drugs have assumed a standard-of-care position in the minds of many health care providers; however, a number of questions remain unresolved in relation to their use. Such questions include issues of mechanism of action, comparability to loop-diuretics in their actions, class-effect, and the basis for their additivity with non-diuretic antihypertensive medication classes. Understanding these issues is important to the effective use of these compounds.
New equations are described that permit the determination of both drug disposition and diuretic response of luminally active diuretics from the analysis of urinary drug excretion data. The methods represent a convenient and logical approach for the clinical study of the disposition of renally excreted drugs that are described by a one-compartment open model and the response of luminally active diuretics that exhibit a linear diuretic excretion rate-response relationship. The validity of the approach is verified in a study of furosemide disposition and response in 10 infants. These methods will facilitate the studies of diuretics in newborn and young infants and other populations that are difficult to study by conventional methodology.
Food significantly affects the pharmacokinetics of oral loop diuretics in healthy individuals, but studies have not been performed in patients with edema. Because of this omission, food's effect on pharmacokinetics has been overlooked and may decrease the pharmacodynamic response in patients who rely on diuretics. Despite this potential interaction, reference manuals do not provide warnings about the effects of food on loop diuretic absorption. We reviewed the published human studies investigating the effects of food on loop diuretics. Peak plasma concentrations and urinary recovery were significantly decreased when taken with food, but only one study showed a corresponding decrease in total urine output, which is likely related to the diuretic threshold effect. These healthy subjects probably were always above the diuretic threshold under both fed and fasting conditions and thus could not augment their urine output. Based on these data in healthy subjects, the special implications for patients who routinely take diuretics are discussed. Therefore, food is more likely to have a clinical effect on the diuretic threshold given its effect in healthy subjects and the special considerations for patients with edema. Additional studies are needed to help answer these questions. Until such data are available, the most conservative, effective clinical approach is to administer oral loop diuretics without food.
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The effects of inorganic salts and of diuretic agents on the excretion of dopamine (DA) were examined in the rat. Both types of treatment evoked significant increases in urinary DA excretion, urine volume and urinary sodium excretion. In the salt-treated animals a significant correlation was observed between DA excretion and urine volume, whereas after diuretic treatment there was better correlation between DA and urinary sodium excretion. The salt-treated animals showed a high correlation between administered chloride and DA excretion. Subcutaneous administration of DA produced a significant diuresis and an increase in sodium excretion. The mechanisms responsible for these responses are discussed with reference to the possibility that DA has a physiological role in the kidney.
In 72 women with a clinical history of frequency and/or urge incontinence and in whom during filling cystometry nearly no abnormalities were detected, cystometry was repeated not by transurethral filling but under high diuretic conditions (diuresis cystometry). The prevalence and strength of detrusor instability, and the prevalence of incontinence were significantly greater during diuresis cystometry compared to filling cystometry. The experiences of these patients during episodes of instability were similar to those in their own daily environment. Most women with motor urge incontinence on filling or diuresis cystometry are losing urine at detrusor pressures lower than would be expected from urethral closure pressure measurements at rest. Therefore, urethral relaxation may have an important role in the etiology of incontinence. Apparent low amplitude detrusor instability may cause severe incontinence when combined with urethral relaxation. Extensive urodynamic investigations (including diuresis cystometry) will improve the clinical applicability of urodynamics.
UNLABELLED: Ascites in patients with cirrhosis of the liver frequently is refractory to diuretic treatment. It was postulated that vasoconstriction of the renal cortex, mediated by activation of the renin-angiotensin-aldosterone-system (RAAS), may be one course of the disturbed sodium- and water-excretion in these patients. We therefore investigated in 14 cirrhotic patients with ascites under constant diuretic treatment the effects of low-dose captopril therapy on urinary sodium- and potassium-excretion, body weight, abdominal girth, serum-sodium, -potassium, creatinine-clearance, plasma-renin-activity (PRA), plasma-aldosterone (PA) and mean arterial pressure (MAP). After a control period of 4 days the patients received 2 x 6.25 mg/d captopril for 5 days and 4 x 6.25 mg/d for further 5 days. Treatment was followed by a second control period without captopril. PRA increased significantly after 2 days of captopril treatment. 2 x 6.25 mg/d captopril induced a significant increase in sodium excretion and a significant decrease of body weight. MAP decreased slightly but significantly without clinical signs of hypotension. 4 x 6.25 mg/d captopril resulted in a further reduction of body weight and a further enhancement of sodium excretion. Three days after withdrawal of captopril sodium output was significantly reduced again. CONCLUSION: In cirrhotic patients low-dose captopril seems to be efficient in the treatment of ascites resistant to diuretics without causing major side effects.