Pharmacologic effects

K⁺-sparing diuretics are so named because, by blocking Na⁺ reabsorption in the cortical collecting duct region of the nephron, they do not produce the hypokalemic effects of the other natriuretic drugs.²⁰ The three drugs of this class—spironolactone, triamterene, and amiloride—are structurally dissimilar (Figure 27-3), but each produces similar effects (mild natriuresis with a decrease in K⁺ excretion) because of the blockade of Na⁺ reabsorption by this pathway.¹¹ Spironolactone is a 17-spirolactone steroid that is structurally similar to aldosterone and functions as an aldosterone antagonist. Triamterene, a pteridine derivative with structural similarities to folic acid, and amiloride, a pyrazine derivative, exert similar effects by directly blocking the apical membrane Na⁺ channels of the principal cells of the collecting duct. By preventing Na⁺ entry into these cells, these diuretics reduce the electrogenic driving force for K⁺ or H⁺ secretion, or both, in this segment. The net effect is a mild diuresis with a K⁺-sparing effect.

FIGURE 27-3 Structural formulas of K⁺-sparing diuretics.

The amount of additional Na⁺ excretion and K⁺ retention is small when drugs of this class are administered alone. When natriuresis from other diuretics is present, the capacity of K⁺-sparing diuretics to inhibit K⁺ excretion is significantly increased. This characteristic provides the rationale for combining loop and thiazide diuretics with a K⁺-sparing diuretic to prevent hypokalemia.

Absorption, fate, and excretion

Spironolactone is administered orally and is rapidly absorbed. The onset of action takes 2 to 4 days, however, and full clinical efficacy is not seen for several weeks. Spironolactone is metabolized by the liver and has two active metabolites, canrenone and canrenoate. Canrenone is prescribed as a K⁺-sparing diuretic in Europe.

Amiloride is given orally, despite its poor gastrointestinal absorption. Diuresis begins within 2 hours, and its duration of action is approximately 24 hours. Amiloride does not undergo metabolism and is excreted unchanged in the urine and feces. Triamterene is better absorbed by the gastrointestinal tract and produces a response within 2 hours of administration. Triamterene has a short plasma half-life and is extensively metabolized to products that are excreted in the urine and feces. The duration of diuresis is longer (approximately 14 hours), however, because the hydroxylated metabolites are also active Na⁺ channel blockers.

Therapeutic uses

K⁺-sparing diuretics are most often used to prevent hypokalemia caused by thiazide and loop diuretics. Spironolactone, triamterene, and amiloride are each available as combination preparations with thiazide diuretics to facilitate this use. Spironolactone is also sometimes used in the treatment of hyperaldosteronism. More recently, spironolactone has been found to be especially useful in the treatment of congestive heart failure (see Chapter 25). Plasma aldosterone concentration is inappropriately elevated in patients with congestive heart failure, and it contributes to the development of edema, direct hypertrophic effects on the myocardium, and other adverse effects in heart failure. Spironolactone effectively antagonizes these effects and has been shown to reduce the mortality rate of patients with congestive heart failure.

Adverse effects

The primary toxic effect of K⁺-sparing diuretics is hyperkalemia. This effect is most common when these drugs are given alone or concomitantly with other inhibitors of K⁺ excretion, such as angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists. Dietary K⁺ supplementation can also precipitate hyperkalemia in patients taking these drugs. Hyperkalemia is infrequent when these drugs are administered in the presence of loop or thiazide diuretics. Spironolactone, because of its steroid structure, can also produce gynecomastia or decreased libido or both in men. Menstrual irregularities have been reported for women. Triamterene and amiloride infrequently cause other effects, such as nausea and vomiting, muscle cramping, and dizziness. Triamterene can sometimes accumulate in the renal pelvis and produce renal stones.

Pharmacologic effects

Thiazide and thiazide-like diuretics enter the lumen of the nephron by glomerular filtration and through secretion by the organic acid transporters of the proximal tubule. Thiazide diuretics can achieve a luminal concentration that is higher than their free plasma concentration. Inhibitors of organic acid transport, such as probenecid, can inhibit the action of thiazide diuretics by lowering the luminal concentration. When the drug reaches the distal convoluted tubule, it binds to the Na⁺-Cl⁻ cotransporter (most likely at the Cl⁻ binding site) and inhibits its turnover (Figure 27-5).¹⁷ The result is a reduction in Na⁺-Cl⁻ reabsorption by the distal convoluted tubule and an increase in the amounts of Na⁺-Cl⁻ delivered to the cortical collecting duct.²² Some of the Na⁺ that is delivered to the collecting duct is excreted with an equivalent amount of water, producing natriuresis and diuresis, and some is reabsorbed in the cortical collecting duct as it is exchanged for K⁺ or H⁺; thiazides also produce kaliuresis (increased excretion of K⁺).

FIGURE 27-5 The action of the thiazide diuretics on the distal convoluted tubule. Na⁺ and Cl⁻ enter the cell from the tubular urine by the electroneutral Na⁺-Cl⁻ cotransporter. Intracellular Na⁺ is removed by the action of basolateral Na⁺,K⁺-ATPase, and Cl⁻ exits through basolateral Cl⁻ channels. Thiazides bind to the Cl⁻-binding site of the Na⁺-Cl⁻ cotransporter, causing an increase in Na⁺-Cl⁻ delivery to more distal tubule segments, increasing Na⁺-Cl⁻ excretion.

In addition to increasing the excretion of Na⁺-Cl⁻ and K⁺, thiazide diuretics increase the reabsorption of filtered Ca⁺⁺. This action distinguishes thiazides from loop diuretics, which promote Ca⁺⁺ excretion. The mechanism for this action is not completely understood, but Ca⁺⁺ reabsorption apparently is increased at the proximal tubule as a result of decreased glomerular filtration (because of reduced plasma volume) and at the distal convoluted tubule as a direct result of Na⁺-Cl⁻ cotransport inhibition. Ca⁺⁺ influx into the distal convoluted cells is governed in part by hormones such as parathyroid hormone, and its efflux is powered by a basolateral Na⁺/Ca⁺⁺ exchanger. Less Na⁺ inside the cell from blockade of apical Na⁺-Cl⁻ cotransport creates a larger gradient for the influx of extracellular Na⁺ through the basolateral Na⁺/Ca⁺⁺ exchanger, resulting in increased Ca⁺⁺ reabsorption. Depending on their structure, some thiazides are also weak inhibitors of carbonic anhydrase; this may result in alkalinization of the urine from increased HCO₃⁻ excretion.

At the level of the whole organism, long-term administration of a thiazide diuretic produces a reduction in the extracellular fluid volume.² The decrease in blood volume activates the renin-angiotensin system, causing angiotensin II–mediated aldosterone release from the adrenal gland. Aldosterone acts on the cortical collecting duct to increase the conductance of the principal cell Na⁺ channels. Blood volume reduction leads to aldosterone-induced increases in the recovery of Na⁺ in the cortical collecting duct, which increases the excretion of K⁺ in this segment further. Thiazides also lead to a long-term decrease in blood pressure. The mechanism for this effect is controversial. A reduction in blood volume would be expected to decrease arterial blood pressure. Blood volume returns to near-normal values, however, after several weeks of thiazide administration. A direct vascular effect—vasodilation caused by reductions in vascular Na⁺ content—has been proposed to explain the continued reduction in total peripheral resistance that persists during thiazide administration.¹⁴

Absorption, fate, and excretion

Absorption of thiazides from the gastrointestinal tract varies with the particular agent. The plasma elimination half-life and duration of diuretic effect for each of the thiazide diuretics are listed in Table 27-2. Plasma protein binding varies considerably among this class of drugs. The parent compounds or metabolites or both are primarily excreted through renal elimination after glomerular filtration and secretion in the proximal tubule.

Therapeutic uses

Thiazide diuretics are primarily used to treat essential hypertension. The Joint National Commission VII and the World Health Organization recommend thiazide diuretics as a first-line treatment for essential hypertension because of their demonstrated efficacy and low cost (see also Chapter 28).