Diuretic Complications

Treatment with thiazide and/or loop diuretics can produce multiple electrolyte abnormalities including hyponatremia, hypokalemia, hypomagnesemia, and metabolic alkalosis. Patients with heart failure usually have elevated ADH levels and urine flow through the distal nephron is reduced due to the low GFR and avid proximal tubule reabsorption. These factors combine to cause persistent concentration of the urine. The maximal urine osmolality achieved by these patients is not as high as that generated by normal subjects given ADH. Patients with heart failure have reduced renal medullary osmotic gradients which reduce maximal concentration. Nonetheless, the urine is often inappropriately concentrated (for the sodium prevailing concentration) and water loads cannot be normally excreted. The contracted EABV and high angiotensin ii levels also stimulate thirst, which exacerbates the tendency to develop, and severity of, hyponatremia. Hyponatremia and hypotonicity would suppress ADH levels in otherwise normal individuals, but the low EABV in patients with CHF causes unrelenting ADH secretion The existance of hyponatremia in patients with heart failure usually indicates that major counterregulatory responses have been triggered, the state of heart failure is advanced, and the prognosis is ominous [17].

Thiazides will often exacerbate the tendency of these patients to develop hyponatremia. These drugs block NaCl reabsorption in the early distal tubule (diluting segment) but do not affect NaCl reabsorption in the TALH which is critical for generating medullary osmotic gradients. Consequently, when patients are treated with thiazides their concentrating capacity is not further com promised but diluting mechanisms are impaired. Thiazide diuresis also stimulates proximal tubule reabsorption which reduces distal delivery of filtrate. This will decrease the quantity of free water which the kidney can generate even in the absence of ADH.

Loop diuretics reduce the kidney's capacity to dilute as well as concentrate the urine. Urine produced by patients receiving loop diuretics tends to become isotonic. Therefore, loop diuretics which reduce both dilution and concentration are less likely to exacerbate hyponatremia than thiazides which do not compromise concentrating capacity. Excessive diuresis with any diuretic will reduce EABV, decrease the GFR, and elevate ADH levels. This will exacerbate the tendency to develop hyponatremia. However, if successful diuresis improves cardiac function, plasma sodium concentrations may return toward normal.

The potassium loss produced by thiazide or loop diuretics results from increased distal tubule delivery of sodium salts and fluid as well as elevated aldosterone levels. High distal tubule flow rates dilutes the intraluminal potassium concentration and thereby improves the gradient for potassium secretion into the tubule. Delivery of large amounts of sodium salts to distal tubules and collecting ducts, which are primed to reabsorb sodium by high aldosterone levels, further accelerates potassium and proton secretion. Elevated ADH levels and metabolic alkalosis also increase distal tubule potassium secretion (see Fig. 8). Hypokalemia is of special concern in patients with heart disease because it increases their risk of severe and life-threatening arrhythmias. This risk is magnified if patients are receiving cardiac glycosides. Hypokalemia will also exacerbate hyponatremia [12], Therefore, hypokalemia and potassium depletion should be avoided and when it does occur in these patients it must be treated aggressively.

A high salt diet results in the delivery of a large quantity of sodium to distal tubule segments where potassium and protons are secreted. This increases renal potassium loss and the tendency to develop hypokalemia. Moderate salt restriction should be combined with diuretic therapy to reduce the severity of this complication. However, extreme dietary salt restriction can also exacerbate potassium losses. This occurs because very low salt intake markedly increases plasma renin activity and produces very high aldosterone levels.

Spironolactone, which blocks the action of aldosterone, or triamterene or amiloride, which block distal tubule sodium reabsorption, will decrease renal tubule potassium and hypokalemia secretion. Therefore, these diuretics are very helpful adjunctive agents. However, when "potassium-sparing" drugs are used in patients with renal insufficiency, the serum chemistries must be carefully monitored to avoid development of severe hyperkalemia.

Angiotensin converting enzyme inhibitors or angiotensin II receptor (ATI) blockers reduce aldosterone levels by decreasing angiotensin II levels or activity. Therefore, these agents also decrease the incidence and severity of diuretic-

FIGURE 8. Mechanisms which increase renal potassium excretion and generate hypokalemia in patients receiving thiazide and/or loop diuretics. ECV, extracellular volume; EABV, effective arterial blood volume; ADH, antidiuretic hormone. (Adapted from Wilcox, C. S. (1989). Chapter 13. Diuretics and potassium. In: The Regulation of Potassium Balance (eds.) Seldin, D. W., and Giebisch, G., Lippencott-Raven, Philadelphia, p. 339.

FIGURE 8. Mechanisms which increase renal potassium excretion and generate hypokalemia in patients receiving thiazide and/or loop diuretics. ECV, extracellular volume; EABV, effective arterial blood volume; ADH, antidiuretic hormone. (Adapted from Wilcox, C. S. (1989). Chapter 13. Diuretics and potassium. In: The Regulation of Potassium Balance (eds.) Seldin, D. W., and Giebisch, G., Lippencott-Raven, Philadelphia, p. 339.

induced hypokalemia and potassium depletion. More importantly, such drugs reduce cardiac afterload and thereby improve cardiac function. This will decrease the levels of the neurohormonal mediators which stimulate renal salt and water retention and thereby decrease diuretic requirements and complications.

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