CHAPTER 27 Diuretic Drugs
The kidney serves the vital function of maintaining fluid and electrolyte homeostasis. Through the processes of glomerular filtration and selective tubular reabsorption and secretion, the kidney maintains plasma volume and the plasma concentration of electrolytes, glucose, amino acids, and other substances within tight physiologic limits, while eliminating metabolic waste products and toxins. The kidneys filter approximately 180 L of plasma each day, one fifth of the cardiac output, producing approximately 1.5 L of urine.
The kidney selectively reabsorbs approximately 99% of the filtered load of water and solute. Many of the filtered solutes are reabsorbed by specific transport proteins located on the luminal membrane of the nephron. When inside of a nephron cell, solute movement back into the plasma is often directly or indirectly coupled to the actions of Na+-K+ activated adenosine triphosphatase (Na+,K+-ATPase) located on the basolateral surfaces of the nephron cells. Transepithelial electrochemical potential differences can also drive the reabsorption of various ions by paracellular pathways.
The reabsorption of water in the kidney is passive, following osmotic gradients created by the movement of solutes along the nephrons to the extent permitted by the water permeability of the various segments of each nephron.10 Water readily equilibrates across the nephron as solute is reabsorbed from the tubular fluid or in response to the medullary osmotic gradient as it descends toward the tip of the loop of Henle. The ascending portion of the nephron is relatively impermeable to water, however.
The selective reabsorption of solute while trapping water in the lumen in these regions creates the dilute tubular fluid that could ultimately become maximally dilute urine. The solute selectively reabsorbed during the passage of tubular fluid through the ascending loop of Henle creates the medullary osmotic gradient that pulls water from the tubular fluid of the descending loop of Henle and the collecting duct. With the exception of the terminal portions of the collecting duct, where urea is recycled from concentrated urine, relatively little net solute reabsorption occurs in this nephron segment. Instead, this is the portion of the nephron that governs water reabsorption.
Antidiuretic hormone (ADH), also known as vasopressin, determines the extent to which this segment is permeable to water.21 If ADH is absent, the tubular fluid that reaches the collecting duct becomes, after some solute exchange, the maximally dilute excreted urine. If the collecting duct is responding maximally to ADH, the most concentrated urine that the kidney can generate is excreted; ADH makes collecting duct cells permeable to water, which permits passive water extraction from the tubular fluid as it passes through the progressively more concentrated osmotic gradient of the medullary interstitium. The more solute that reaches the collecting duct, the greater is the volume of urine for any amount of ADH.
All the drugs discussed in this chapter affect renal function by inhibiting the reabsorptive capacity of the renal nephrons. This action produces an increase in the rate of urine production. Substances that increase the quantity of urine are called diuretics. Many substances produce this effect, including caffeine, alcohol, and water itself; however, most clinically useful diuretics produce their effects by inhibiting Na+ reabsorption by the nephrons.10 Such drugs are properly called natriuretics; even so, in most circumstances, all these drugs are referred to as diuretics. All clinically useful diuretics produce their effects by acting at specific segments of the nephron. Common conditions for which diuretics are used include essential hypertension and congestive heart failure.5,15,17,18
This discussion of diuretics proceeds up the nephron in a retrograde direction. As shown in Figure 27-1, this order of consideration moves from diuretics with a low maximal effect to diuretics with a high maximal effect. The effects of blockade of Na+ reabsorption upstream on tubular fluid composition are acted on by downstream mechanisms—mechanisms that act to limit or offset these effects. The effects of the various classes of diuretics on urine volume, urine pH, and urine electrolytes are summarized in Table 27-1.
FIGURE 27-1 Sites of action of diuretics along the nephron. The percentages shown illustrate the approximate amount of the filtered load of Na+ that is reabsorbed by each nephron segment. Each diuretic, with the exception of spironolactone, acts on the tubular lumen to produce its effect.
The pathway by which Na+ is reabsorbed in the late distal tubule/cortical collecting duct is shown in Figure 27-2. The apical membrane of these cells contains Na+ channels. The entry of Na+ through these channels carries a net positive charge along with it (i.e., Na+ entry is electrogenic), leaving the lumen with a net negative charge. This negative charge in the lumen acts as a driving force for movement in the opposite direction of other cytosolic cations such as K+ and H+ by the collecting duct (see Figure 27-2), resulting in Na+ retention and K+ excretion. Aldosterone, acting through nuclear receptors in the principal cells of the cortical collecting duct, enhances the conductance of apical Na+ channels. For a given amount of aldosterone, more Na+ delivered to this site means more Na+ reabsorption and more K+ secretion, a coupled process referred to as Na+/K+ exchange.3 Because of the Na+/K+ exchange at this portion of the nephron, any diuretics acting further upstream to block Na+ reabsorption and increase distal Na+ delivery result in enhanced urinary excretion of K+.
FIGURE 27-2 Actions of K+-sparing diuretics in the cortical collecting duct. In this segment, Na+ is transported passively through channels located on the apical membranes of principal cells. The conductance of this channel is enhanced by an aldosterone-induced protein (AIP). The apical entry of Na+ (removal of positive charges) creates a negative electrostatic driving force in the tubule lumen that enhances the secretion of K+ from principal cells and H+ from type A intercalated cells. Amiloride and triamterene are antagonists of apical membrane Na+ channels, producing a mild natriuresis and preventing K+ excretion in this segment. Spironolactone, by antagonizing the action of aldosterone, prevents AIP activation of Na+ conductance, producing natriuresis with a K+-sparing effect. ADP, Adenosine diphosphate; ATP, adenosine triphosphate.
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.
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.
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.
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.
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.
Benzothiazide diuretics (commonly referred to as thiazides) are derived from 1,2,4-benzothiadiazine-7-sulfonamide 1,1 dioxide (Figure 27-4). Chlorothiazide was originally synthesized in an attempt to produce more potent carbonic anhydrase inhibitors. Investigators soon observed that although chlorothiazide produced prompt diuresis as predicted, it did not do so by increasing the excretion of NaHCO3. Rather, it produced a large increase in the excretion of NaCl, suggesting a novel natriuretic and diuretic mechanism: inhibition of Na+-Cl− cotransport in the distal nephron.22 Structural congeners of chlorothiazide, including hydrochlorothiazide, hydroflumethiazide, and methyclothiazide, also share this mechanism. Several other compounds (chlorthalidone, indapamide, metolazone, and quinethazone) that are not structurally related to thiazides also inhibit renal Na+-Cl− cotransport and produce natriuresis and diuresis that is indistinguishable from thiazides. For this reason, it is a common convention to refer to all drugs that inhibit renal Na+-Cl− cotransport as “thiazides” regardless of their structure.
Table 27-2 lists diuretics of the thiazide class available for prescription in the United States. Hydrochlorothiazide is also available in combination form with K+-sparing diuretics (Table 27-3). In addition, there are at least 21 formulations on the market that combine hydrochlorothiazide with another antihypertensive drug.
|PROPRIETARY (TRADE) NAME||THIAZIDE||ADDITIONAL DRUG|
|Moduretic||Hydrochlorothiazide 50 mg||Amiloride 5 mg|
|Aldactazide, Spirozide||Hydrochlorothiazide 25 mg||Spironolactone 25 mg|
|Aldactazide||Hydrochlorothiazide 50 mg||Spironolactone 50 mg|
|Maxzide||Hydrochlorothiazide 25 mg||Triamterene 37.5 mg|
|Hydrochlorothiazide 50 mg||Triamterene 75 mg|
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 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.
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).