Lasix Induced Bicarbonate Alterations

The use of loop diuretics is commonly associated with the development of metabolic alkalosis (Fig. 2). Loop diuretics inhibit salt transport in the thick ascending limb of Henle, resulting in a reduction in the extracellular fluid volume. The contraction of extracellular fluid around a fixed concentration of bicarbonate will cause the bicarbonate concentration to rise. This effect has been called a contraction alkalosis. The magnitude by which this mechanism contributes to the alkalosis is small, however, as a result of intracellular buffering. Both release of hydrogen ions by cell buffers and increased uptake of bicarbonate into bone tend to minimize the rise in bicarbonate concentration induced by volume contraction. A much more important mechanism by which loop diuretics induce metabolic alkalosis is related to the ability of these drugs to increase net acid excretion in the distal nephron, thereby increasing the renal input of new bicarbonate. At the same time, these agents lead to alterations in the renal handling of bicarbonate in the proximal nephron such that the rise in serum bicarbonate is sustained. Stated differently, loop diuretics lead to the gen-

Loop diuretics Thiazide diuretics

Loop diuretics Thiazide diuretics

Loop Diuretics Metabolism The Liver
figure 2. The generation and maintenance of metabolic alkalosis induced by loop and thiazide diuretics.

eration of a metabolic alkalosis by increasing acidification in the distal nephron. At the same time, these drugs maintain the alkalosis by enhancing bicarbonate reclamation in the proximal nephron.

The generation of metabolic alkalosis through increased net acid excretion in the distal nephron is the result of indirect effects induced by the loop diuretics. Diuretic-induced volume contraction leads to secondary hyperaldosteron-ism. At the same time distal delivery of sodium is increased due to the direct effects of the diuretic in the thick limb of Henle. Aldosterone-mediated sodium reabsorption increases the luminal electronegativity of the collecting duct and results in increased hydrogen ion secretion. Hydrogen ion secretion is also directly stimulated by aldosterone. Diuretic-induced hypokalemia also contributes to increased distal hydrogen ion secretion as the activity of the H/K ATPase is increased in the setting of hypokalemia. As net acid excretion increases, newly generated bicarbonate is added to the venous blood.

In addition to increasing hydrogen ion secretion in the collecting duct, loop diuretics have also been shown to increase hydrogen ion secretion in the thick ascending limb of Henle. In this segment, bicarbonate reabsorption is mediated by a Na/H antiporter located on the apical membrane. Loop diuretics secondarily stimulate the activity of the antiporter by inhibiting NaCl entry across the luminal membrane, lowering cell Na, and increasing the transmembrane Na gradient. The quantitative importance of increased HC03 reabsorption in this segment to the overall increase in distal hydrogen ion secretion is unknown but may be greater than previously thought.

Secondary effects of the loop diuretics also account for the increased capacity of the proximal tubule to reclaim bicarbonate and thereby maintain the alkalosis. Diuretic-induced reductions in effective arterial blood volume decrease the glomerular filtration rate and lower the filtered load of bicarbonate. A decrease in effective circulatory volume is also associated with increased activity of the Na/H antiporter. Diuretic-induced potassium depletion can also affect the kidney's ability to maintain metabolic alkalosis. Potassium depletion can lead to further decreases in glomerular filtration rate and filtered load of bicarbonate. In addition, potassium depletion has been demonstrated to stimulate rates of proximal and distal tubular hydrogen secretion. Furthermore, hypokalemia stimulates ammonia production, thereby providing for increased buffer capacity for ongoing hydrogen ion secretion distally. While these effects of potassium depletion on acid-base balance would be predicted to both generate and maintain metabolic alkalosis, potassium depletion only mildly increases the plasma bicarbonate concentration in humans. The blunted rise in serum bicarbonate concentration is accounted for by an inhibitory effect of hypokalemia on aldosterone secretion. This effect will inhibit renal acidification. A final factor which serves to maintain diuretic-induced alkalosis is an increase in the pC02 concentration. In the setting of metabolic alkalosis, the increase in pH is attenuated by a rise in the pC02 which results from compensatory hypoventi-

lation. This hypoventilatory response to metabolic alkalosis is limited by the development of hypoxemia such that the pC02 concentration rarely exceeds 50-55 mm Hg.

Metabolic alkalosis is not a typical baseline feature of the clinical conditions in which loop diuretics are most commonly used. Nevertheless, these conditions are commonly associated with the development of metabolic alkalosis once diuretic therapy is initiated. In addition, the alkalosis tends to develop rapidly and can be large in magnitude. For example, cirrhosis, congestive heart failure, and nephrotic syndrome are all characterized by a contracted effective arterial blood volume. In the basal state, circulating aldosterone levels are already increased but distal sodium delivery is low. Initiation of diuretic therapy allows for the increased circulating levels of aldosterone to be coupled to increased distal sodium delivery, resulting in stimulated distal acidification. Newly generated bicarbonate is readily reclaimed in the proximal nephron as these patients already have a contracted effective arterial blood volume.

The rapid development of metabolic alkalosis in the edematous states after initiation of loop diuretic therapy should be contrasted to what happens in an otherwise normal individual given loop diuretics. In a euvolemic salt replete individual the development of metabolic alkalosis tends to be much more gradual in onset and less severe. In this circumstance, baseline aldosterone levels are normal and begin to increase only once the diuretic achieves some degree of volume depletion. It is only at this point that increased distal sodium delivery becomes coupled to increased circulating levels of aldosterone and generation of a metabolic alkalosis is initiated. The ability to maintain the alkalosis is directly related to the degree of volume depletion which is determined by dietary intake of salt, dose of diuretic, and frequency of administration. The ingestion of a large sodium diet serves to minimize any decrease in volume induced by the diuretic, thereby impairing the ability to maintain the alkalosis. By contrast, a diet overly restricted in sodium would exacerbate the contraction in extracellular fluid volume and allow for the alkalosis to be maintained. By similar mechanisms, large doses of loop diuretics given at more frequent intervals would tend to increase those factors involved in both the generation and the maintenance of metabolic alkalosis.

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