Recent Studies on the Characterization of Loop Diuretics

Giebisch, Gerhard; Klein-Robbenhaar, Geertruida

doi:10.1097/00005344-199322003-00002

Cited by 11 publications

(17 citation statements)

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“…The loop diuretics' main site of activity is at the loop of Henle, where reabsorption of approximately 20%-30% of the total filtered sodium is inhibited. In response to initial diuresis, enhanced reabsorption of sodium and water at distal sites occurs through cellular hypertrophy and activation of neurohormonal homeostatic mechanisms [19,20]. This distal compensation plays a critical role in the development of diuretic tolerance.…”

Section: Pharmacologymentioning

confidence: 99%

“…& p . 1 : Loop diuretics act mainly in the thick ascending limb of Henle's loop [18,[20][21][22]. Sodium and chloride reabsorption at the loop of Henle is achieved through several pathways.…”

Section: Renal Effectsmentioning

confidence: 99%

“…One such pathway is the Na + /K + /2Cl − cotransport system present in the apical cell membrane of the thick ascending limb ( Fig. 1) [18,[20][21][22]. The Na + /K + /2Cl − cotransporter moves sodium out of the tubular lumen and into the tubule cell down a concentration gradient.…”

Section: Renal Effectsmentioning

confidence: 99%

“…Sodium reabsorption also occurs via paracellular transport that is driven by the lumen-positive transepithelial potential difference created by tubule cell polarization [20]. Polarization of the tubule cell occurs when potassium leaves the cell via potassium conductance channels in the luminal membrane, and chloride leaves the cell via chloride conductance channels and potassium chloride cotransporters in the basilar membrane [18].…”

Section: Renal Effectsmentioning

confidence: 99%

“…1 : Loop diuretics do not inhibit sodium reabsorption in the distal nephron segments [18]. Instead distal segments are most likely responsible for the diminishing potency of loop diuretics, a phenomenon known as diuretic tolerance [19,20]. Furosemide given continuously to rats without saline replacement resulted in "normalization" of sodium excretion after initial diuresis [19].…”

Section: Renal Effectsmentioning

confidence: 99%

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The clinical pharmacology of loop diuretics in the pediatric patient

Eades

Christensen

1998

Pediatric Nephrology

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The loop diuretics furosemide and bumetanide are frequently employed in the pediatric population for the management of fluid overload in both acute and chronic disease states. They act mainly by inhibiting sodium reabsorption in the nephron at the thick ascending limb of Henle's loop. Important pharmacokinetic differences between adults and infants include a reduced clearance and prolonged half-life, that may cause accumulation of these agents to potentially toxic levels if dosing intervals are not adjusted. Unfortunately, little is known about the time required for maturation of loop diuretic elimination in older infants, children, and adolescents. Similar to adults, limited pharmacodynamic evidence in neonates suggests that a maximally efficient diuretic dose exists. Increasing the diuretic dose beyond this maximum does not offer further benefit, but may increase the risk of toxicity. Common problems encountered in the pediatric patient as well as in adults are loop diuretic tolerance and resistance. Loop diuretic dosing strategies aimed at overcoming these phenomena include administration by continuous infusion, coadministration with albumin, and coadministration with metolazone or thiazides. This article reviews the pharmacology, pharmacokinetics, and pharmacodynamics of furosemide and bumetanide in pediatric patients. A better understanding of the clinical pharmacology of the loop diuretics should aid clinicians in the development of dosing regimens aimed at producing adequate diuresis without promoting excessive diuretic tolerance.

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Section: Pharmacologymentioning

confidence: 99%

Section: Renal Effectsmentioning

confidence: 99%

Section: Renal Effectsmentioning

confidence: 99%

Section: Renal Effectsmentioning

confidence: 99%

Section: Renal Effectsmentioning

confidence: 99%

See 3 more Smart Citations

The clinical pharmacology of loop diuretics in the pediatric patient

Eades

Christensen

1998

Pediatric Nephrology

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Interaction of the diuretics torasemide and U-37883A with the KATP channel in rat isolated aorta

Löffler-Walz

Quast

1998

Naunyn-Schmiedeberg's Arch Pharmacol

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In this study we have investigated the interaction of the loop diuretics torasemide and furosemide and of the eukalemic diuretic U-37883A (4-morpholinocarboximidine-N-1-adamantyl-N'-cyclohexylhyd rochloride) with the ATP-sensitive K+ channel (K(ATP) channel) in rat aortic rings. Torasemide contains a sulphonylurea group which might enable the compound to interfere with K(ATP) channels; this group is lacking in furosemide. U-37883A blocks several types of K(ATP) channels. The interaction with the vascular K(ATP) channel was probed in binding studies, 86Rb+ efflux experiments and vasorelaxation assays. Torasemide inhibited the binding of the K(ATP) channel inhibitor [3H]glibenclamide and of the opener [3H]P1075 with IC50 values of 19 and 45 microM, respectively; furosemide and U-37883A were inactive or interfered with binding in a nonspecific way. In 86Rb+ efflux experiments, the loop diuretics, at microM concentrations, inhibited basal tracer efflux to 50% whereas U-37883A had no effect. P1075-stimulated 86Rb+ efflux, a qualitative measure of K(ATP) channel opening, was inhibited by U-37883A and torasemide with IC50 values of 0.06 and 130 microM, respectively; furosemide induced only a small (23%) inhibition. In experiments measuring isometric force, torasemide and furosemide partially relaxed endothelium-denuded aortic rings precontracted with noradrenaline or KCl with EC50 values between 6 and 10 microM. The vasorelaxant effect of P1075 was inhibited in a noncompetitive manner by torasemide (300 microM) but unaffected by furosemide. U-37883A increased noradrenaline-induced force and inhibited the vasorelaxant effect of P1075 in an apparently competitive manner with an inhibition constant of 0.4 microM. The data show that torasemide interferes specifically with the binding of the K(ATP) channel modulators [3H]glibenclamide and [3H]P1075 and with the K(ATP) channel opening and vasorelaxant effects of P1075 whereas furosemide is inactive. This suggests that the interaction of torasemide with the vascular K(ATP) channel is due to the sulphonylurea group present in torasemide. U-37883A, which does not inhibit P1075 binding, is one of the most potent blockers of P1075-induced 86Rb+ efflux yet described but is relatively weak as an inhibitor of P1075-mediated vasorelaxation. The opposite vascular actions of torasemide and U-37883A are expected to contribute to the renal effects of these drugs.

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Torasemide is an effective diuretic in the newborn rabbit

Dubourg

Mosig

Drukker

et al. 2000

Pediatric Nephrology

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The effect of intravenous (i.v.) torasemide on diuresis and renal function was evaluated in three groups of normoxemic, 5- to 10-day-old, newborn New Zealand White rabbits. The animals of group 1 received 0.2 mg/kg of torasemide i.v., whereas in group 2 an i.v. dose of 1.0 mg/kg was given. The third group of animals received a bolus i.v. dose of 1.0 mg/kg torasemide with continuous i.v. replacement of estimated urinary fluid and electrolyte losses. Torasemide proved to be an effective, potassium-sparing diuretic, without significant effect on glomerular filtration rate (GFR). Renal blood flow (RBF) fell and the renal vascular resistance (RVR) rose in all three groups of animals, although the rise in RVR in group 3 was not significant. These changes in renal hemodynamics were most pronounced in the animals of group 2 and are probably secondary to torasemide-induced hypovolemia (2.8% loss of body weight) and accompanying humoral reactions, such as an increase in angiotensin II (not measured). When the latter is prevented by simultaneous re-infusion of an electrolyte solution (group 3), replacing urinary losses, GFR increases and the changes in RBF and RVR are blunted. We conclude that torasemide is an effective, potassium-sparing diuretic in newborn rabbits. No evidence was found for a vasodilatory action of the drug.

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Recent Studies on the Characterization of Loop Diuretics

Cited by 11 publications

References 0 publications

The clinical pharmacology of loop diuretics in the pediatric patient

The clinical pharmacology of loop diuretics in the pediatric patient

Interaction of the diuretics torasemide and U-37883A with the KATP channel in rat isolated aorta

Torasemide is an effective diuretic in the newborn rabbit

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