Pharmacodynamic and kinetic considerations on diuretics as a basis for differential therapy

Knauf, H.; Mutschler, E.

doi:10.1007/bf01666849

Cited by 22 publications

(22 citation statements)

References 38 publications

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“…It is striking, however, that the same linear functions, which meet the O-point of the GFR-axis, have now been demonstrated for the thiazides (Fig. 2) [16]. Even for the antikaliuretic amiloride, the natriuretic and K + sparing effect is also demonstrable down to endstage renal failure [17].…”

Section: Pharmacokinetic Pharmacodynamic Interrelationships Of Diureticsmentioning

confidence: 83%

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Low-dose segmental blockade of the nephron rather than high-dose diuretic monotherapy

Knauf

Mutschler

1993

Eur J Clin Pharmacol

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The specific renal effect of diuretics is due to the fact that their concentrations is almost 100-fold greater in the renal tubule than in the plasma. The function of the different segments of the nephron may be altered following changes in the effective arterial blood volume (EABV) and the extracellular fluid volume (ECFV). In diseases with reduced EABV, e.g., congestive heart failure, decompensated cirrhosis of the liver, and the nephrotic syndrome, proximal tubular hyperreabsorption of sodium occurs, leaving only a low Na+ load in the distal segments of the nephron, the site of diuretic action. Clinically, the response to diuretics is reduced or resistance to diuretics may even ensue, which can be predicted by a FENa < 0.2%. Resistance to diuretics can be overcome by short-term comedication with acetazolamide, which increases Na+ delivery to the site of action of the other diuretics used concomitantly. In states with increased ECFV, e.g. in chronic renal failure, there is distal tubular Na+ rejection, leading to a greater increase in FENa the more GFR is reduced. The remaining intact nephrons present a relatively increased response to diuretics. The efficacy of diuretic treatment in renal failure can be optimised by combining loop diuretics with thiazides. In conclusion, low-dose combination therapy, inducing "segmental blockade of the nephron", meets the functional changes along the nephron. It is therefore more effective and safer than high-dose monotherapy.

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Section: Pharmacokinetic Pharmacodynamic Interrelationships Of Diureticsmentioning

confidence: 83%

“…3). During their maximal effect loop diuretics increase FENa up to 8 % at normal GFR, and up to 24 % in end-stage renal disease [1,16]. Thiazides increase FEN, to 3 and 15 %, respectively [13], and even the antikaliuretic amiloride doubles FEN, both at normal GFR and in end-stage renal failure [16].…”

Section: Fena and Gfr: "Magnification Phenomenon"mentioning

confidence: 99%

Low-dose segmental blockade of the nephron rather than high-dose diuretic monotherapy

Knauf

Mutschler

1993

Eur J Clin Pharmacol

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“…The diuretic effects of loop diuretics have been widely studied and reported [6,8,16]. This review will concentrate on comparative studies with furosemide and torasemide.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

“…These drugs differ con siderably in their pharmacokinetic properties, particularly in renal failure (table 1). Elimina tion of furosemide and piretanide depend on their renal clearance [6], In renal failure, they Bumetanide is mainly eliminated via the kidneys in patients with normal renal func tion. In renal failure, its renal clearance is decreased, but total plasma clearance and elimination half-life are constant because of an increase in extrarenal elimination.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Comparative Pharmacokinetics and Pharmacodynamics of Loop Diuretics in Renal Failure

et al. 1994

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Loop diuretics increase the fractional excretion of volume, sodium, potassium, chloride and calcium in all stages of renal failure, and their potency is directly correlated with these excretory activities. Tubular secretion of loop diuretics in renal failure is impaired both by reduced renal blood flow and by reduced activity of the tubular carrier system. For these reasons, high concentrations of diuretics in the peritubular capillaries are necessary to guarantee delivery of sufficient drug to their site of action in the ascending limb of the loop of Henle. Piretanide and furosemide have a constant extrarenal elimination and thus accumulate in renal failure. Decreased renal excretion of bumetanide is compensated by hepatic elimination and hence bumetanide does not accumulate. Elimination of torasemide is also independent of its renal excretion. Thus in renal failure, torasemide is the only loop diuretic in which the plasma concentration is strictly dose dependent. Loop diuretics follow a number of different metabolic pathways, but this may not be clinically relevant.

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“…vanced renal failure, the maximal fractional excretion of sodium achieved by loop diuret ics was 25% [4] and that with the addition of a thiazide [3] was 15%. The FENa could be dou bled by the addition of amiloride [4,5].…”

Section: Qualitative Differences Of Responses To Diuretics In Renal Fmentioning

confidence: 99%

Functional State of the Nephron and Diuretic Dose-Response - Rationale for Low-Dose Combination Therapy

Knauf

Mutschler²

1994

Cardiology

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The functions of the different nephron segments follow changes in the effective arterial blood volume and the extracellular fluid volume. In syndromes with reduced effective arterial blood volume, for example congestive heart failure, decompensated hepatic cirrhosis and nephrotic syndrome, hyperreabsorption of sodium in the proximal tubule reduces the sodium load in the more distal segments of the nephron. As this is a major site of sodium excretion, reduction in the response to a diuretic may be predicted by a reduced fractional excretion of sodium ( < 0.2%). Such diuretic resistance may be overcome with acetazolamide, which increases delivery of sodium to the distal tubule. In syndromes with increased extracellular fluid volume, such as chronic renal failure, distal tubular rejection of sodium leads to a progressive increase in its fractional excretion as the glomerular filtration rate is reduced. The remaining intact nephrons exhibit a relatively increased response to diuretics. The efficacy of loop diuretics in renal failure can be optimized by combination with thiazides. The latter prevent early distal tubular hyperreabsorption following diuretic-induced blockade of sodium transport in the loop of Henle. For these reasons, low-dose combinations of different diuretics induce ‘segmental nephron blockade’ and are, therefore, potentially more clinically effective and safer than high doses of single compounds.

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Pharmacodynamic and kinetic considerations on diuretics as a basis for differential therapy

Cited by 22 publications

References 38 publications

Low-dose segmental blockade of the nephron rather than high-dose diuretic monotherapy

Low-dose segmental blockade of the nephron rather than high-dose diuretic monotherapy

Comparative Pharmacokinetics and Pharmacodynamics of Loop Diuretics in Renal Failure

Functional State of the Nephron and Diuretic Dose-Response - Rationale for Low-Dose Combination Therapy

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