Introduction

When a diuretic drug is first administered to a normal individual or to a patient with an edematous disorder (see Fig. 1), rates of urinary sodium and chloride excretion usually increase above baseline, leading to a period of negative sodium and chloride balance. This natriuresis (and chloriuresis) is a hallmark of effective diuretic therapy of edema. Yet within several days to several weeks, net daily solute and water losses decline and eventually approach prediuretic levels despite continued drug administration. These changes in diuretic responsiveness result from adaptive processes that occur during diuretic therapy in every individual. When these processes become manifest once the desired extracellular fluid (ECF) volume has been attained, they are clinically useful and prevent progressive ECF volume contraction. When these same processes develop prior to achieving the desired ECF volume, they would be viewed as contributing to diuretic resistance. Because specific therapeutic approaches can be devised to overcome these adaptations, an understanding of renal adaptations to diuretic treatment is crucial for a rational approach to the diuretic resistant patient. This chapter will categorize adaptations to diuretic treatment according to the time at which they develop. Immediate adaptations limit the intrinsic potency of diuretic drugs; they occur during the initial diuretic-induced

Diuretic Agents: Clinical Physiology and Pharmacology

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FIGURE 1. Effects of diuretics on urinary Na excretion and extracellular fluid volume. (Inset) Effect of diuretic on body weight, taken as an index of extracellular fluid volume. Note that steady state is reached within 6-8 days despite continued diuretic administration. (Main graph) Effects of loop diuretic on urinary Na excretion. Bars represent 6-hr periods before (in Na balance) and after doses loop diuretic (D). The dotted line indicates dietary Na intake. The solid portion of bars indicates the amount by which Na excretion exceeds intake during natriuresis. The hatched areas indicated the amount of positive Na balance after the diuretic effect has worn off. Net Na balance during 24 hr is the difference between the hatched area (postdiuretic NaCI retention) and the solid area (diuretic-induced natriuresis). Chronic adaptation is indicated by progressively smaller peak natriuretic effects (the braking phenomenon) and is mirrored by a return to neutral balance, as indicated in the inset. As discussed in the text, chronic adaptation requires ECF volume depletion.

Chronic Adaptation 'The Braking Phenomenon'

Dietary Na Intake (140 mmol/day)

Short Term Adaptation 'Post-Diuretic NaCI Retention'

FIGURE 1. Effects of diuretics on urinary Na excretion and extracellular fluid volume. (Inset) Effect of diuretic on body weight, taken as an index of extracellular fluid volume. Note that steady state is reached within 6-8 days despite continued diuretic administration. (Main graph) Effects of loop diuretic on urinary Na excretion. Bars represent 6-hr periods before (in Na balance) and after doses loop diuretic (D). The dotted line indicates dietary Na intake. The solid portion of bars indicates the amount by which Na excretion exceeds intake during natriuresis. The hatched areas indicated the amount of positive Na balance after the diuretic effect has worn off. Net Na balance during 24 hr is the difference between the hatched area (postdiuretic NaCI retention) and the solid area (diuretic-induced natriuresis). Chronic adaptation is indicated by progressively smaller peak natriuretic effects (the braking phenomenon) and is mirrored by a return to neutral balance, as indicated in the inset. As discussed in the text, chronic adaptation requires ECF volume depletion.

natriuresis and generally result from intrinsic renal processes. Short-term adaptations occur after the initial effect of the diuretic drug has worn off and may result from both systemic and intrarenal processes. Chronic adaptations occur only when diuretic drugs have been administered during a long period of time (weeks to months). Because diuretic resistance is most commonly observed in patients who have received high doses of diuretic during a long period of time, these chronic adaptations may be especially relevant to the phenomenon of diuretic resistance in patients.

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Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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