K + Depletion and the Progression of Hypertensive Disease or Heart Failure

After the introduction of chlorothiazide in 1958,1 as the first of many sulfonamide thiazide diuretics, these orally active diuretics rapidly became the cornerstone for treatment of patients with congestive heart failure (CHF) and other edematous states. These diuretics were also widely adopted for primary or adjuvant antihypertensive drug therapy. Since the beginning, it was recognized that such natriuretic-diuretic therapy in both of these disorders is regularly accompanied by demonstrable body potassium and magnesium deficiencies, often reflected by significant, albeit generally mild, observed decrements in plasma K+ and Mg2+ levels. But because no particular problems were recognized with broad use of these diuretics, over the years physicians became increasingly sanguine about their occurrence. Accordingly, thiazide diuretics and then, beginning in 1966, the similar but more powerful loop diuretics (eg, furosemide) also became broadly used as primary or adjuvant treatments for high blood pressure and for the edematous state of CHF, cirrhosis with ascites, and nephrotic syndrome.The first selective aldosterone receptor antagonist, spironolactone (Aldactone), was introduced in clinical medicine in 1958.2 By blocking the action of aldosterone, it proved to be a potent natriuretic-diuretic and K+-retaining agent. Thus, it produced diuresis and weight loss with no loss of K+ or Mg2+, something our group views as a great conceptual therapeutic advantage over thiazides. The lack of any demonstrable morbidity from thiazide-induced K+ depletion and the impressive prompt diuresis that these drugs produced at a low cost, however, carried the sulfonamide diuretics into a leadership position for treatment of hypertension or edematous states that continues today.Our preference for the aldosterone antagonist approach, however, was enhanced by 2 facts. First, in outpatient trials, in >20 reports of head-to-head comparisons of spironolactone with a thiazide diuretic, spironolactone proved to be at least as …