Diuretic Drugs

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Chapter 21 Diuretic Drugs

MAJOR DRUG CLASSES

Osmotic diuretics

Carbonic anhydrase inhibitors

Thiazide diuretics

Loop diuretics

K⁺-sparing diuretics

Abbreviations
ATP	Adenosine triphosphate
ECF	Extracellular fluid
ENaC	Epithelial Na⁺ channel
GFR	Glomerular filtration rate
GI	Gastrointestinal
IV	Intravenous
NCC	Na⁺/Cl⁻ cotransporter protein
NHE3	Na⁺/H⁺ exchange (antiport) protein
NKCC2	Na⁺/K⁺/2Cl⁻ cotransporter protein

Therapeutic Overview

The term diuretic classically refers to an agent that increases the rate of urine flow. However, on the basis of this definition, water is a diuretic because its ingestion is followed by an enhanced rate of urine production. Nevertheless, the diuresis induced by water is not accompanied by a substantial increase in the excretion of electrolytes, which distinguishes it from the effects of the agents described in this chapter. The primary effect of diuretics is an increase in solute excretion, mainly Na⁺ salts. The increase in urine flow is secondary and is a response to the osmotic force of the additional solute within the tubule lumen. Drugs that increase the net urinary excretion of Na⁺ salts are called natriuretics.

Despite variations in dietary salt intake, the kidneys adjust the excretion of Na⁺ and water to maintain the extracellular fluid (ECF) volume within narrow limits. In pathophysiological states, a deleterious expansion of the ECF leads to edema, characteristic of congestive heart failure, cirrhosis of the liver, nephrotic syndrome, and renal failure. Dietary Na⁺ restriction is the mainstay of treatment; however, frequently, ECF expansion persists and diuretic drugs are needed. The prevalence of edema-forming states in clinical medicine has led to the widespread use of diuretics to enhance excretion of salts (mainly NaCl) and water.

Diuretics are used in treatment of edema to normalize the volume of the ECF compartment without distorting electrolyte concentrations. The size of the ECF compartment is largely determined by the total body content of Na⁺, which, in turn, is determined by the balance between dietary intake and excretion. When Na⁺ accumulates faster than it is excreted, ECF volume expands. Conversely, when Na⁺ is lost faster than it is ingested, ECF volume will be depleted. Diuretics produce a transient natriuresis and reduce total body content of Na⁺ and the volume of the ECF. The effect is moderated, however, after 1 to 2 days, when a new equilibrium is attained. At this time a balance between intake and excretion is achieved, and body weight stabilizes. This “braking” phenomenon, in which there is refractoriness to effects of the diuretic, is

not a true tolerance but results from activation of compensatory salt-retaining mechanisms. Specifically, contraction of the ECF volume activates the sympathetic nervous system (see Chapter 19), with a resultant increase in release of angiotensin II, aldosterone, and antidiuretic hormone that may lead to a compensatory increase in Na⁺ reabsorption. Moreover, continued delivery of Na⁺ to more distal nephron segments induced by loop diuretics,

Therapeutic Overview
Goal: To increase excretion of salt and water
Thiazide Diuretics	K⁺-sparing Diuretics
Hypertension	Chronic liver failure
Congestive heart failure (mild)	Congestive heart failure, when hypokalemia is a problem
Renal calculi	Carbonic Anhydrase Inhibitors
Nephrogenic diabetes insipidus	Cystinuria (to alkalinize tubular urine)
Chronic renal failure (as an adjunct to loop diuretic)	Glaucoma (to decrease intraocular pressure)
Osteoporosis	Periodic paralysis that affects muscle membrane function
Loop Diuretics	Acute mountain sickness (to counteract respiratory alkalosis)
Hypertension, in patients with impaired renal function	Metabolic alkalosis
Congestive heart failure (moderate to severe)	Osmotic Diuretics
Acute pulmonary edema	Acute or incipient renal failure
Chronic or acute renal failure	Reduce intraocular or intracranial pressure (preoperatively)
Nephrotic syndrome
Hyperkalemia
Chemical intoxication (to increase urine flow)

and its compensatory reabsorption, may lead to structural hypertrophy of these cells, thereby enhancing Na⁺ reabsorption.

In addition to the treatment of edema, diuretics are also efficacious in other disorders including hypertension, nephrogenic diabetes insipidus, hyponatremia, nephrolithiasis, hypercalcemia, and glaucoma. The therapeutic applications of these compounds are presented in the Therapeutic Overview Box.

Mechanisms of Action

All diuretics promote natriuresis and diuresis to reduce ECF volume; however, their mechanisms and sites of action differ. The five major types of diuretics are listed in Table 21-1, and their primary sites of action on the nephron are depicted in Figure 21-1. Knowledge of the mechanisms and sites of action of these agents is important in selecting an appropriate drug and anticipating and preventing complications. In addition, because each class of drugs exerts effects at specific targets, a combination of two or more drugs will often result in additive or synergistic effects to affect the reabsorption or excretion of Na⁺, Cl⁻, , water, and, to some extent, K⁺, H⁺, and organic ions. To understand the mechanisms and consequences of the actions of the diuretics, a basic knowledge of renal physiology is essential.

TABLE 21–1 Sites and Mechanisms of Action of Diuretics

FIGURE 21–1 The nephron, depicting its location, segments, and the sites of action of different classes of diuretics.

Renal Function and Regulation

Renal Epithelial Transport and Nephron Function

The normal human glomerular filtration rate (GFR) is approximately 180 L/day. Assuming a normal plasma Na⁺ concentration of 140 mmol/L, that means that 25,200 mmol of Na⁺ are filtered each day. To maintain Na⁺ balance, the kidney must reabsorb more than 99% (24,950 mmol) of the filtered load of Na⁺. This staggering amount of solute and water reabsorption is achieved by the actions of the million nephrons in each human kidney. Renal epithelial cells transport solute and water from the apical cell membrane to the basolateral cell membrane. The polarization of structures that differentiate the apical membrane from the basolateral membrane allows the vectorial transport of solute and water (Fig. 21-2). The basolateral cell membrane expresses the ubiquitous Na⁺/K⁺-adenosine triphosphatase (ATPase) (the Na⁺ pump) that exchanges 3 Na⁺ ions for 2 K⁺ ions, resulting in decreased intracellular Na⁺ providing a chemical gradient and an electronegative cell interior for Na⁺ entry from the lumen through the apical membrane (a potential difference of approximately 60 mV), which also attracts Na⁺. The concentration gradient then favors passive efflux of the K⁺ that entered the cell to the intercellular space. Because the ECF concentration of K⁺ is low relative to Na⁺, a recycling of K⁺ between the cell and interstitial fluid is necessary to maintain the Na⁺ pump.

FIGURE 21–2 Polarized renal epithelial cells. Distinct transporters are present in apical cell and basolateral cell membranes to mediate the net transepithelial transport of Na⁺ and water. Operation of the basolateral cell membrane Na⁺/K⁺-ATPase (1) initiates the movement of Na⁺ and water by decreasing the intracellular Na⁺ concentration (2) and maintaining a negative interior potential in the cell. Na⁺ enters the cell from the lumen (3) down an electrochemical gradient via three types of transport mechanisms: channel (A), symport (B) in which X may be glucose, amino acids, or PO₄, and antiport (C).

The transport of Na⁺ across the apical cell membrane adjacent to the tubular fluid is achieved by passive diffusion via proteins that form a pore or channel (see Fig. 21-2, A), and two types of carrier-mediated transport, a cotransport (symport) pathway that transports Na⁺ and another solute species (such as Cl⁻ or amino acids) in the same direction (see Fig. 21-2, B), and a countertransport (antiport) pathway that transports Na⁺ and another solute species (H⁺) in the opposite direction (see Fig. 21-2, C). In each case the low intracellular Na⁺ concentration as a consequence of the action of the Na⁺/K⁺-ATPase pump provides the electrochemical gradient for Na⁺ entry.

This transepithelial transport causes the osmolality of the lateral intercellular spaces to increase as a result of the accumulation of solute, producing an osmotic gradient that permits water to flow by two routes (see Fig. 21-2):

• Transcellular water flow in segments that are permeable to water

• Paracellular water flow (between cells, through tight junctions) in which solute is carried as a result of solvent drag

In the primary pathway of water flow, water moves from lumen to cell to interstitial fluid to capillary, as a direct result of the transepithelial osmotic gradient.

Tubular Reabsorption: Transport by the Proximal Tubule

The GFR of healthy adults ranges from 1.7 to 1.8 mL/min/kg, and approximately two thirds of the water and NaCl filtered at the glomerulus is reabsorbed by the proximal tubule. , glucose, amino acids, and other organic solutes are also reabsorbed. When GFR increases, salt and water excretion increases, but fractional reabsorption in the proximal tubule does not change. This is termed glomerulotubular balance. It moderates but does not entirely eliminate the effects of alterations in the GFR on salt and water excretion.

The transport of Na⁺, , and Cl⁻ is important for the actions of several diuretics on the proximal tubule. Na⁺ is reabsorbed primarily with in the early proximal tubule, whereas Na⁺ is reabsorbed primarily with Cl⁻ in the late proximal tubule (Fig. 21-3). At the apical cell membrane of the early proximal tubule, Na⁺ entry is coupled with H⁺ efflux via the Na⁺/H⁺ antiporter (NHE3), which is a protein containing 10 to 12 transmembrane spanning domains and a hydrophilic C-terminal domain and is subject to regulation by a variety of factors, including angiotensin II, which increases its activity. H⁺ extruded from the cell combines with to form H₂CO₃, which rapidly forms CO₂ and water in the presence of the enzyme carbonic anhydrase. CO₂ rapidly enters the cell via simple diffusion and is rehydrated to form carbonic acid. Because the concentration of cellular H⁺ is low, the reaction proceeds as follows: CO₂ + H₂O → H₂CO₃ → H⁺ + . Thus a constant supply of H⁺ is furnished for countertransport with Na⁺. that accumulates is cotransported with Na⁺ across the basolateral cell membrane into the interstitial fluid and, subsequently, into the blood. Although the cytoplasmic hydration reaction occurs spontaneously, the rate is inadequate to allow reabsorption of the load filtered (approximately 4000 mEq/day). However, little or none of the filtered is excreted because of the presence of carbonic anhydrase. The net effect of coupling of the Na⁺/H⁺ antiporter to the carbonic anhydrase-mediated hydration and rehydration of CO₂ is preservation of . The final step is its transfer from the interstitial fluid into peritubular capillaries.

FIGURE 21–3 Ion transport in early and late proximal tubule cells. CA, Carbonic anhydrase; NHE3, the Na⁺/H⁺ exchange protein.

In the late proximal tubule (see Fig. 21-3), Na⁺ is reabsorbed primarily with Cl⁻. Reabsorption is secondary to activation of both the NHE3, which couples inward Na⁺ transport with outward H⁺ transport, and a Cl⁻ base (formate) exchanger that transports Cl⁻ from lumen to cell in exchange for a base. The parallel operation of both exchangers results in net Na⁺ and Cl⁻ absorption by the late proximal tubule. Passive transport of Na⁺ and Cl⁻ also occurs between cells through the paracellular pathway.

Reabsorptive transport systems of the proximal tubule deliver large amounts of fluid and solutes to the interstitial space, which raises pressure in the interstitium. For reabsorption to continue, pressure must be decreased. The permeable peritubular capillary can easily carry away reabsorbed fluids and solutes. Pushed by interstitial pressure and pulled by the oncotic pressure of intracapillary proteins (higher in postglomerular than in preglomerular capillaries), filtered fluid and solutes return to the blood.

In summary, the proximal tubule reabsorbs approximately 70% of filtered water, Na⁺, and Cl⁻, 85% of filtered , and 50% of filtered K⁺ (Table 21-2). These percentages are relatively constant, even when filtered quantities increase or decrease. As a result, minor fluctuations in GFR do not influence fluid and electrolyte excretion very much. The driving force for reabsorption of water and electrolytes is the Na⁺/K⁺-ATPase. Passive movements of other ions and water are initiated and sustained by active transport of Na⁺ across basolateral cell membranes. Osmotic equilibrium with plasma is maintained to the end of the proximal tubule. Most of the filtered is not actually reabsorbed directly from the lumen; rather, it is converted to CO₂ and water in the vicinity of the brush border membranes, within which large concentrations of carbonic anhydrase are located. The direction of this reaction is H₂CO₃ → CO₂ + H₂O (established by the high concentration of carbonic acid in luminal fluid resulting from the secretion of H⁺). Carbonic anhydrase in the cytoplasm catalyzes formation of carbonic acid. Cellular H⁺ is then exchanged for luminal Na⁺, and is reabsorbed across the basolateral cell membranes. In this indirect way, filtered is reabsorbed.

TABLE 21–2 Summary of Reabsorption in the Proximal Tubule^*

Tubular Reabsorption: Transport by the Loop of Henle

Diuretics have no discernible actions in the descending limb of the loop of Henle. These cells permit water to diffuse from the lumen to the medullary interstitium, where higher osmotic pressures are encountered, but they do not contain specialized transport systems and are relatively impermeable to Na⁺ and Cl⁻.

In contrast, the thick ascending limb and its transport functions are an important site of action of the loop (also called high-ceiling) diuretics (Fig. 21-4). Approximately 25% to 35% of filtered Na⁺ and Cl⁻ is reabsorbed by the loop of Henle. The Na⁺/K⁺-ATPase in the basolateral membrane provides the gradient for Na⁺ and Cl⁻ absorption. Na⁺ entry across the apical membrane is mediated by an electroneutral transport protein that binds one Na⁺, one K⁺, and two Cl⁻ ions and is referred to as the Na⁺/K⁺/2Cl⁻ (NKCC2) cotransporter. Although the ascending limb is highly permeable to Na⁺, K⁺, and Cl⁻, it is impermeable to water. Thus the continuous reabsorption of these ions without reabsorption of water dilutes the luminal fluid, thus the name diluting segment. Na⁺ entry down an electrochemical gradient drives the uphill transport of K⁺ and Cl⁻. This system depends on the simultaneous presence of these three ions in the luminal fluid. Once inside the cell, K⁺ passively reenters the lumen (K⁺ recycling) via conductive K⁺ channels in the apical membrane. Cl⁻, on the other hand, exits the cell via conductive Cl⁻ channels in the basolateral membrane. Depolarization of the basolateral membrane occurs as a consequence of Cl⁻ efflux, creating a lumen-positive (relative to the interstitial fluid) transcellular potential difference of approximately 10 mV. This drives paracellular cation transport, including Na⁺, Ca⁺⁺, and Mg⁺⁺. Inhibition of the NKCC2 cotransporter not only results in excretion of Na⁺ and Cl⁻ but also in excretion of divalent cations, such as Ca⁺⁺ and Mg⁺⁺.

FIGURE 21–4 Ion transport by thick ascending limb cells. This segment, also referred to as the diluting segment, is impermeable to water, and thus the tubular lumen concentration of ions decreases.

Based on its molecular structure, the NKCC2 cotransporter belongs to a family referred to as electroneutral Na⁺/Cl⁻ cotransporters, which also includes the Na⁺/Cl⁻ cotransporter (NCC) sensitive to thiazide diuretics. These proteins have a structure similar to NHE3 and appear to be up regulated by reduction of intracellular Cl⁻ activity and cell shrinkage. Bartter’s syndrome (a renal tubular disorder) type I kindreds apparently have mutations in the gene encoding the NKCC2 transporter; Types II and III of this syndrome result from mutations in channels. The well-recognized countercurrent mechanism in the renal medulla depends on the activity of this cotransport system, and drugs that inhibit this pathway diminish the ability of the kidney to excrete urine that is either more concentrated or more dilute than plasma.

In summary, fluid is reabsorbed from the lumen of the descending limb of the loop as it progresses deeper into the medullary areas of higher osmotic pressure. Electrolyte concentrations increase to a maximum at the bend and gradually decrease as the NKCC2 cotransport mechanism and Na⁺ pump, working in tandem, achieve reabsorption of Na⁺, K⁺, and Cl⁻. The thick ascending limb reabsorbs 25% of filtered NaCl and 40% of filtered K⁺, but not water, whereas the entire loop reabsorbs 15% of the fluid.

Tubular Reabsorption: Transport by the Distal Convoluted Tubule

In contrast to the proximal tubule and loop of Henle, there is less reabsorption of water and electrolytes in the distal convoluted tubule. It reabsorbs approximately 10% of the filtered load of NaCl. Similar to the thick ascending limb, this segment is impermeable to water, and the continuous reabsorption of NaCl further dilutes tubular fluid. NaCl entry across the apical membrane is mediated by the electroneutral NCC cotransporter sensitive to thiazide diuretics (Fig. 21-5). Unlike the NKCC2 cotransporter of the thick ascending limb, this cotransporter does not require participation of K⁺. As in other segments, the basolateral Na⁺/K⁺-ATPase provides the low intracellular Na⁺ concentration that facilitates downhill transport of Na⁺. The distal tubule does not have a pathway for K⁺ recycling, and therefore the transepithelial voltage is near zero. Therefore the reabsorption of Ca⁺⁺ and Mg⁺⁺ is not driven by electrochemical forces. Instead, Ca⁺⁺ crosses the apical membrane via a Ca⁺⁺ channel and exits the basolateral membrane via the NCC exchanger. Thus, by inhibiting the NCC cotransporter, thiazide diuretics indirectly affect Ca⁺⁺ transport through changes in intracellular Na⁺. Another mechanism of increased Ca⁺⁺ reabsorption with thiazide diuretics is an increase in the intracellular concentrations of Ca⁺⁺-binding proteins.

FIGURE 21–5 Ion transport by the distal convoluted tubule cell. As in the case for the thick ascending limb, this segment is relatively impermeable to water.

Recently, inactivating mutations have been found in the human gene encoding the NCC transporter in patients with Gitelman’s syndrome, characterized by hypotension, hypokalemia, hypomagnesemia, and hypocalciuria, similar to the effects of thiazides. Pseudohypoaldosteronism type II is an autosomal dominant disease characterized by hypertension, hyperkalemia, and sensitivity to thiazide diuretics. It has been suggested that an activating mutation of the NCC cotransporter is responsible. Recently, two protein kinases have also been linked to the pathogenesis of this syndrome. They are found in the distal nephron and are thought to control the activity of the cotransporters.

Tubular Reabsorption: Transport by the Collecting Tubule

The collecting tubule is the final site of Na⁺ reabsorption, and approximately 3% of filtered Na⁺ is reabsorbed by this segment. Although the collecting tubule reabsorbs only a small percentage of the filtered load, two characteristics are important for diuretic action. First, this segment is the site of action of aldosterone, a hormone controlling Na⁺ reabsorption and K⁺ secretion (see Chapter 39). Second, virtually all K⁺ excreted results from its secretion by the collecting tubule. Thus the collecting tubule contributes to the hypokalemia induced by diuretics.

The collecting tubule is composed of two cell types with separate functions. Principal cells are responsible for the transport of Na⁺, K⁺, and water, whereas intercalated cells are primarily responsible for the secretion of H⁺ or . Intercalated cells are of two types, A and B, the former responsible for secretion of H⁺ via an H⁺-ATPase (primary active ion pump) in the apical cell membrane, and the latter responsible for secretion of via a Cl⁻/ exchanger in the apical membrane. In contrast to more proximal cells, the apical membrane of principal cells does not express cotransport or countertransport systems; rather it expresses separate channels that permit selective conductive transport of Na⁺ and K⁺ (Fig. 21-6). Na⁺ is reabsorbed through a conductive Na⁺ channel. The low intracellular Na⁺ as a result of the basolateral Na⁺/K⁺-ATPase generates a favorable electrochemical gradient for Na⁺ entry through epithelial Na⁺ channels (ENaCs). Because Na⁺ channels are present only in the apical cell membrane of principal cells, Na⁺ conductance causes depolarization, resulting in an asymmetrical voltage across the cell and a lumen-negative transepithelial potential difference. This, together with a high intracellular-to-lumen K⁺ gradient, provides the driving force for K⁺ secretion.

FIGURE 21–6 Ion transport by principal cells of the collecting tubule. The principal cell contains both Na⁺ and K⁺ channels in the apical cell membrane. The Na⁺ channel depolarizes the membrane and provides an asymmetrical transepithelial voltage profile that favors K⁺ secretion.

The molecular identity of this amiloride-sensitive Na⁺ channel has recently been determined with the cloning of ENaC. These channels are composed of three subunits, α, β, and γ, with 30% homology between them. It has been proposed that ENaC is a heterotetrameric protein, αβαγ, regulated by several factors including hormones, such as vasopressin, oxytocin, signaling elements, such as G proteins and cyclic adenosine monophosphate (cAMP), and intracellular ions (Na⁺, H⁺, and Ca⁺⁺). These hormones alter Na⁺ reabsorption by either increasing the number of channels expressed at the cell surface or by increasing conductance by increasing the probability of open channels, not by increasing single channel conductance.

Mutations of ENaC could result in either gain of function, as in Liddle’s syndrome, associated with hypertension and hypokalemia, or loss of function, as in pseudohypoaldosteronism, associated with hypotension and hyperkalemia. The amount of Na⁺ and K⁺ in the urine is tightly controlled by aldosterone, which acts on principal cells after release from the adrenal cortex. Aldosterone penetrates the basolateral membrane of principal cells and binds to a cytosolic mineralocorticoid receptor (Fig. 21-7), where its activation causes the receptor-aldosterone complex to translocate to the nucleus to induce formation of specific messenger ribonucleic acids (RNAs) encoding proteins that enhance Na⁺ conductance in apical cell membranes and Na⁺/K⁺-ATPase activity in basolateral cell membranes. As a result, transepithelial Na⁺ transport is increased, further depolarizing the apical membrane. An increase in the lumen-negative potential, in turn, enhances K⁺ secretion through K⁺ channels in the apical membrane. The final equilibratory steps take place in medullary collecting tubules, where small amounts of NaCl and K⁺ are reabsorbed. In the presence of antidiuretic hormone, water is transported out of the lumen into the interstitium. The direction of water movement is determined by the medullary tonicity established by the countercurrent mechanism. A quantitative summary of the fractional reabsorption of water and Na⁺ of each tubule segment is shown in Figure 21-8. The proximal tubule reabsorbs more Na⁺ than water; the entire distal tubule and medullary collecting system reabsorbs less than 5% of filtered Na⁺.

FIGURE 21–7 Effects of aldosterone. The principal cell is the primary target for aldosterone, which binds to cytoplasmic receptors, causing them to translocate into the nucleus and initiate synthesis of new proteins (aldosterone-induced proteins [AIPs]). AIPs induce newly synthesized Na⁺ channels and Na⁺/K⁺-ATPase and increase the translocation of existing transporters from the cytosol to the surface membrane.

FIGURE 21–8 Summary of renal reabsorption of filtered H₂O (A) and Na⁺ (B) in a 70-kg human.

Tubular Secretion and Bidirectional Transport of Organic Acids and Bases

Except for osmotic agents and competitive aldosterone inhibitors, all diuretics in clinical use release or accept an H⁺ at the pH of body fluids and are subsequently secreted into the proximal tubular lumen. Thus these drugs exist as both uncharged molecules and charged organic ions, and H⁺ concentrations in body fluids determine the nature of drug transport and action.

The proximal tubular secretion of diuretic anions and cations into tubular fluid illustrates the influence of electrical charge on drug delivery to their sites of action and on their rapid decline in plasma. Two generic systems that transport organic ions from blood to urine reside in the proximal tubule. One transports organic acids (anions as the A⁻ form of acid HA), and the other transports organic bases (cations as BH⁺ form) of base B (see Chapter 2). Their chief characteristics are as follows:

• At least one step is active and against the concentration gradient, although energy is furnished indirectly.

• They are saturable.

• They are susceptible to competitive inhibition by other organic ions.

The lack of specific structural requirements supports the idea that these two mechanisms underlie the urinary excretion of many endogenous and environmental chemicals. Many of these are solutes of low molecular weight that bind to plasma proteins and thus are not filtered through glomerular membranes. In addition to most of the diuretics, organic acids and bases that are secreted include acetylcholine and choline, bile acids, uric acid, para-aminohippuric acid, epinephrine, norepinephrine, histamine, antibiotics, and morphine.

The tubular transport of organic acids and bases is illustrated in Figure 21-9. Organic anions (OA⁻) are taken up by the basolateral cell membrane through indirect coupling to Na⁺ (see Fig. 21-9, A). The Na⁺/K⁺-ATPase maintains a steep inward Na⁺ gradient, which provides energy for entry of Na⁺-coupled dicarboxylate (α-ketoglutarate). The operation of a parallel dicarboxylate/OA⁻ exchange drives the uphill movement of OA⁻ into the cell. The cell is now loaded with OA⁻, which enters the lumen by facilitated diffusion. The mechanism may involve anion exchange or conductive transport.

FIGURE 21–9 Transport of organic anions (A) and cations (B). OA⁻, Organic anion; OC⁺, organic cation; αKG²⁻, α-ketoglutarate.

Organic cations (OC⁺) gain entry from the interstitial fluid across basolateral cell membranes (Fig. 21-9, B). Their entry is aided by carrier-facilitated diffusion. Once inside the cell, OC⁺ enter the lumen through countertransport with H⁺. The operation of this cation exchange is dependent on the parallel operation of the Na⁺/H⁺ antiporter, NHE3.

Osmotic Diuretics

Osmotic diuretics are unique because they do not interact with receptors or directly block a renal transport mechanism. Their activity depends entirely on the osmotic pressure they exert in solution.

Mannitol, urea, glycerol, and isosorbide are the primary osmotic diuretics, with mannitol most widely used (Fig. 21-10). Mannitol produces a diuresis secondary to (1) an increase in osmotic pressure in the proximal tubule fluid and loop of Henle, which retards passive reabsorption of water, and (2) an increase in renal blood flow and washout of medullary tonicity. Glomerular filtration of mannitol into the tubular fluid retards passive water reabsorption primarily by the proximal tubule and thin limbs of the loop of Henle. In effect, the osmotic force of nonreabsorbable solute in the lumen opposes the osmotic force of reabsorbable Na⁺. The isosmolality of urine is preserved because mannitol molecules replace reabsorbed Na⁺. The reabsorbed fraction of water is reduced, increasing the amount of water entering the loop of Henle. The luminal concentration of Na⁺ decreases when Na⁺ is transported and water fails to follow it, resulting in a change in Na⁺ concentration gradient and a backward flux of Na⁺ into the lumen, with ultimately a small increase in excretion. Over zealous administration of mannitol may result in hypernatremia, hyperkalemia, and volume depletion.

FIGURE 21–10 Structures of members of the five major classes of diuretic drugs.

Mannitol diffuses from the blood into the interstitial space, where the increased osmotic pressure draws water from the cells to increase ECF volume. This increases medullary renal blood flow, which washes out the medullary osmotic gradient created by countercurrent forces. Thus the NaCl concentration in the thick ascending limb is reduced, indirectly diminishing the efficiency of the NKCC2 cotransport system and decreasing transport of Na⁺ and water. Ascending limb cells are thus an important site of natriuretic action.

Carbonic Anhydrase Inhibitors

Acetazolamide, the prototypical carbonic anhydrase inhibitor (see Fig. 21-10), has limited use as a diuretic. It is used primarily to reduce intraocular pressure in glaucoma and to treat metabolic alkalosis because of its ability to enhance excretion.

Carbonic anhydrase is a metalloenzyme in high concentrations in renal proximal tubule cells, ciliary processes of the eye, red blood cells, choroid plexus, intestine, and pancreas. There are five mammalian isozymes, of which two are relevant to its action in the proximal tubule. Type IV is expressed in basolateral and apical cell membranes, and type II is expressed in cytoplasm. Carbonic anhydrase catalyzes hydration of CO₂ and dehydration of carbonic acid, as follows:

(21-1)

The prevailing direction of the reaction is established by pH; normally CO₂ is hydrated, resulting in H⁺ generation. The H⁺ is then exchanged for Na⁺, which enters the cell.

Acetazolamide inhibition of carbonic anhydrase reduces H⁺ concentration in the tubule lumen and decreases availability of H⁺ for Na⁺/H⁺ exchange. There is a resulting increase in and Na⁺ in the proximal portion of the lumen (see Figs. 21-1 and 21-3). Although some is reabsorbed at other tubular sites, approximately 30% of the filtered load appears in the urine after carbonic anhydrase inhibition. A hyperchloremic metabolic acidosis results from depletion, which renders subsequent doses of acetazolamide ineffective.

Thiazide Diuretics

Thiazide diuretics, such as hydrochlorothiazide (see Fig. 21-10), were developed to identify compounds that increase excretion of Na⁺ and Cl⁻ rather than Na⁺ and , as occurs with carbonic anhydrase inhibitors. The major site of action of the thiazides is the distal convoluted tubule (see Figs. 21-1 and 21-5), where they inhibit electroneutral NaCl absorption. The distal convoluted tubules also express high-affinity receptors for thiazides.

Thiazide diuretics inhibit Na⁺ and Cl⁻ transport in distal tubules, increasing delivery to more distal portions of the nephron, where a small fraction of excess Na⁺ is reabsorbed and replaced with K⁺. Because only 15% or less of the glomerular filtrate reaches the distal tubule, the magnitude of the effects of the thiazides is more limited than with drugs acting in the thick ascending limb. The distal tubule is relatively impermeable to water absorption, which contributes to urinary dilution; therefore urinary dilution is impaired in the presence of thiazide diuretics.

In addition to enhancing Na⁺ and Cl⁻ excretion, thiazide diuretics contribute to urinary excretion of other ions. Chlorothiazide can inhibit transport by the proximal tubule as a consequence of its ability to inhibit carbonic anhydrase; most other thiazides are only weak carbonic anhydrase inhibitors.

Thiazide diuretics decrease Ca⁺⁺ excretion, unlike the loop diuretics, which increase Ca⁺⁺ excretion. Sustained decreases in Ca⁺⁺ excretion resulting from the long-term administration of thiazide diuretics are accompanied by mild elevations in serum Ca⁺⁺. As a consequence, these agents are useful for management of nephrolithiasis and osteoporosis. The mechanisms that contribute to this include effects on Ca⁺⁺ transport at both proximal and distal tubules.

Thiazide diuretics enhance Mg⁺⁺ excretion by unknown mechanisms, and long-term use can lead to hypomagnesemia. Thiazides can cause urate excretion to be reduced, and this can lead to hyperuricemia. ECF volume contraction also plays a role.

Loop Diuretics

Loop diuretics generate larger responses than those produced by thiazides. Acting on the thick ascending limb, loop diuretics can inhibit the reabsorption of as much as 25% of the glomerular filtrate (Fig. 21-11) and are often effective when thiazides do not suffice. Despite their efficacy, loop diuretics are remarkably safe when used properly.

FIGURE 21–11 Dose-response curves comparing Na⁺ excretion after administration of thiazides or loop diuretics.

Four loop diuretics are available in the United States: ethacrynic acid, furosemide, torsemide, and bumetanide. Ethacrynic acid and furosemide are prototypes of loop I and II drugs, respectively. Bumetanide is considerably more potent and differs pharmacokinetically but is otherwise similar to the older drugs. Furosemide (see Fig. 21-10) inhibits reabsorption of Na⁺ and Cl⁻ by the thick ascending limb by competing with Cl⁻ for a binding site on the NKCC2 cotransporter. Ethacrynic acid reacts with sulfhydryl groups, a reaction formerly considered to precede diuresis. However, this is no longer thought to be the case, because several natriuretic compounds with similar structures do not react with sulfhydryl groups. Ethacrynic acid also inhibits Na⁺/K⁺-ATPase but only in excessive concentrations. Because the loop of Henle is responsible for accomplishing the countercurrent multiplication that generates a concentrated medullary interstitium, loop diuretics prevent formation of a concentrated urine.

In addition to their ability to enhance Na⁺ and Cl⁻ excretion, loop diuretics also enhance Ca⁺⁺ and Mg⁺⁺ excretion. Because transepithelial Na⁺ and Cl⁻ transport through the NKCC2 cotransporter elaborates a lumen-positive potential, furosemide inhibits this transporter and reduces the potential. This reduces the gradient for passive Mg⁺⁺ and Ca⁺⁺ absorption through paracellular pathways.

Under Na⁺-replete conditions, loop diuretics produce an increase in GFR and a redistribution of blood from medulla to cortex. The increase in GFR results in part from release of vasodilatory prostaglandins. GFR is also controlled by tubuloglomerular feedback. This system relies on a unique anatomical arrangement, where a segment of nephron is juxtaposed between afferent and efferent arterioles of the glomerulus. This segment, the macula densa, lies between the cortical thick ascending limb and the distal convoluted tubule. The apical cell membrane of macula densa cells expresses a furosemide-sensitive NKCC2 cotransporter. Tubular fluid flow is somehow sensed by macula densa cells, which causes afferent arterioles to constrict and GFR to decrease. There is evidence that Na⁺ and Cl⁻ transport by the NKCC2 cotransporter is the critical sensing step, because furosemide abolishes tubuloglomerular feedback and increases GFR. This suggests that inhibition of tubuloglomerular feedback by furosemide participates in producing an increase in GFR.

Loop diuretics reach their sites of action by first entering the tubular fluid through proximal tubular secretion. Drugs that block tubular secretion (e.g., probenecid) influence the temporal response to diuretics but do not abolish their effects.

Potassium-Sparing Diuretics

The K⁺-sparing diuretics comprise three pharmacologically distinct groups: steroid aldosterone antagonists, pteridines, and pyrazinoylguanidines. Their site of action is the collecting tubule, where they interfere with Na⁺ reabsorption and indirectly with K⁺ secretion (see Figs. 21-1 and 21-6). Their diuretic activity is weak because fractional Na⁺ reabsorption in the collecting tubule usually does not exceed 3% of the filtered load. For this reason K⁺-sparing drugs are ordinarily used in combination with thiazides or loop diuretics to restrict K⁺ loss and sometimes augment diuretic action.

Spironolactone and eplerenone, analogs of aldosterone and its major metabolite, canrenone, bind to mineralocorticoid receptors in the kidney and elsewhere, acting as competitive inhibitors of aldosterone (see Chapter 39). Aldosterone antagonists decrease Na⁺ conductance at the apical membrane of principal cells, thereby reducing the lumen-negative potential. This results in a decrease in the electrical gradient for K⁺ secretion.

Triamterene (see Fig. 21-10) and amiloride are structurally different from spironolactone but have the same functional effects. Both drugs are organic bases secreted into the lumen by proximal tubular cells, and both block the apical membrane Na⁺ channel of principal cells and reduce Na⁺ conductance (see Fig. 21-7). Similar to spironolactone, they cause the lumen-negative potential and the electrical gradient for K⁺ secretion to be abolished. Although they are weak diuretics and natriuretics, K⁺ is conserved. Amiloride also blocks Na⁺/H⁺ exchange, Na⁺/Ca⁺⁺ exchange, and Na⁺/K⁺-ATPase, but it blocks the Na⁺ channel at therapeutic doses only. Amiloride also decreases Ca⁺⁺ and H⁺ excretion, also as a consequence of a decrease in the lumen-negative potential.

Pharmacokinetics

The pharmacokinetic parameters of the diuretic agents are summarized in Table 21-3.

TABLE 21–3 Pharmacokinetic Parameters

Mannitol is not readily absorbed from the gastrointestinal (GI) tract and is administered by the IV route. It distributes in ECF and is excreted almost entirely by glomerular filtration, with approximately 90% appearing in the urine within 24 hours. Less than 10% is reabsorbed by the renal tubule, and an equal amount is metabolized in the liver.

Isosorbide and glycerol are administered orally to reduce intraocular pressure before ophthalmological surgical procedures.

Urea is administered IV as an aqueous solution containing dextrose, or invert sugar, and is rarely given by mouth because it induces nausea and emesis. Urea, glycerol, and isosorbide are metabolized extensively.

The several thiazides differ considerably with respect to their pharmacokinetics and pharmacodynamics. Hydrochlorothiazide, the most commonly prescribed compound in the United States, has a bioavailability of approximately 70%. It has a large apparent volume of distribution and a rapid onset of action. Unlike hydrochlorothiazide, GI absorption of chlorothiazide is dose dependent. As a group, thiazide diuretics have longer half-lives compared with loop diuretics and are mostly prescribed once a day. Indapamide, chlorthalidone, and polythiazide have the longest half-lives. Plasma protein binding varies from 10% to 95%. Free drug enters the tubular fluid by filtration and organic acid secretion and reaches its site of action via the distal convoluted tubular fluid.

The highly lipid-soluble members of the thiazide family possess larger apparent volumes of distribution and lower renal clearances. Indapamide, bendroflumethiazide, and polythiazide are primarily metabolized in the liver, and the major route of elimination is by glomerular filtration and proximal tubular secretion of unchanged drug.

Absorption of administered doses of furosemide from the GI tract is good but could vary from 10% to 100%. Bumetanide and torsemide have better absorptions in the range of 80% to 100%. Furosemide is practically insoluble in lipid and almost totally bound to plasma protein. Furosemide is excreted unchanged as well as after conjugation to glucuronic acid by the kidney. A significant proportion of bumetanide and torsemide is metabolized in the liver.

Ethacrynic acid, administered IV, has a rapid onset and is rapidly excreted. It is conjugated with glutathione, forming an ethacrynic acid-cysteine adduct more potent than the parent drug. Because ethacrynic acid is poorly lipid soluble, its apparent volume of distribution is small. Plasma protein binding is extensive, and the compound and its metabolites are excreted in urine by filtration and proximal tubule secretion. Elimination by the intestine is augmented through biliary transport, and this accounts for approximately one third of the administered dose.

Acetazolamide is well absorbed from the GI tract. More than 90% of the drug is plasma protein bound. Because it is relatively insoluble in lipid, acetazolamide does not readily penetrate cell membranes or cross the blood-brain barrier. The highest concentrations are found in tissues that contain large amounts of carbonic anhydrase (e.g., renal cortex, red blood cells). Renal effects are noticeable within 30 minutes and are usually maximal at 2 hours. Acetazolamide is excreted rapidly by glomerular filtration and proximal tubular secretion; methazolamide is absorbed more slowly.

Spironolactone is discussed in Chapter 39. Triamterene has good bioavailability and is metabolized in the liver to an active metabolite, which is excreted in the urine. The half-life of this active metabolite increases in renal insufficiency but is unchanged in liver disease.

Amiloride is not metabolized and is excreted in the urine; renal insufficiency increases its half-life.

Relationship of Mechanisms of Action to Clinical Response

Osmotic Diuretics

Mannitol is the osmotic agent of choice because its properties best satisfy the requirements of an efficient osmotic diuretic. It is nontoxic, freely filtered through glomeruli, essentially nonreabsorbable from tubular fluid, and not readily metabolized. Urea, glycerol, and isosorbide are less efficient because they penetrate cell membranes. Consequently, as urea, glycerol, or isosorbide is reabsorbed, luminal concentrations decrease, and the tendency to retain filtered fluid diminishes. Mild hyperkalemia may develop acutely in patients treated with mannitol. Mannitol may also produce a modest excretion of K⁺, , PO₄⁻³, Ca⁺⁺, and Mg⁺⁺.

Mannitol has been administered prophylactically to prevent acute renal failure associated with severe trauma, cardiovascular and other complicated surgical procedures, or therapy with cisplatin and other nephrotoxic drugs. Mannitol does not increase GFR or renal blood flow in humans.

Because osmotic drugs reduce the volume and pressure of the aqueous humor by extracting fluid from it, they are used for short-term treatment of acute glaucoma. Similarly, infusions of mannitol are used to lower the elevated intracranial pressure caused by cerebral edemas associated with tumors, neurosurgical procedures, or similar conditions. Osmotic agents redistribute body fluids, increase urine flow rate, and accelerate renal elimination of filtered solutes, which are often the goals for treatment for many clinical disorders. Mannitol is occasionally used to promote renal excretion of bromides, barbiturates, salicylates, or other drugs after overdoses.

Carbonic Anhydrase Inhibitors

Acetazolamide is used to treat chronic open-angle glaucoma. Because aqueous humor has a high concentration, it is used to reduce aqueous humor formation. Acetazolamide is also used to prevent or treat acute mountain sickness, to alkalinize the urine, and to treat metabolic alkalosis. Carbonic anhydrase inhibitors are occasionally used to treat epilepsy. During the past several years the popularity of carbonic anhydrase inhibitors as diuretics has waned because tolerance develops rapidly, increased urinary excretion of results in development of systemic acidemia, and more effective and less toxic agents have been developed. Nevertheless, acetazolamide is administered for short-term therapy, especially in combination with other diuretics, to patients who are resistant to other agents.

Thiazide Diuretics

In general, thiazide diuretics are used in treatment of hypertension, congestive heart failure, and other conditions in which a reduction in ECF volume is beneficial. Many large clinical studies have proved the efficacy and tolerability of these agents in treatment of hypertension. As a result, this class of diuretics is recommended as monotherapy or in combination with other agents in treatment of hypertension. The blood pressure reduction in patients with hypertension results in part from contraction of the ECF volume (see Chapter 20). This occurs acutely, leading to a decrease in cardiac output with a compensatory elevation in peripheral resistance. Vasoconstriction then subsides, enabling cardiac output to return to normal. Augmented synthesis of vasodilator prostaglandins has been reported and may be a crucial factor for long-term maintenance of a lower pressure, even though ECF volume tends to return toward normal.

In addition to their use in the treatment of edematous disorders and hypertension, thiazide diuretics are also used in other disorders. Because they decrease renal Ca⁺⁺ excretion, they are used in the treatment of Ca⁺⁺ nephrolithiasis and osteoporosis. Thiazide diuretics are also used in the treatment of nephrogenic diabetes insipidus, where tubules are unresponsive to vasopressin and patients undergo a water diuresis. Often the volume of dilute urine excreted is large enough to lead to intravascular volume depletion, if it is not offset by an adequate intake of fluid. Chronic administration of thiazides increases urine osmolality and reduces flow. The mechanism hinges on excretion of Na⁺ and its removal from the ECF, which contracts ECF volume. The proximal tubule then avidly reabsorbs Na⁺. Urine flow rate diminishes and urine osmolality increases when Na⁺ transport in the distal convoluted tubule is inhibited. Drug therapy in this instance is most effective when used in combination with dietary salt restriction.

Loop Diuretics

Loop diuretics are very efficacious at low dosages. NaCl losses are equivalent to those obtained with thiazides; at high doses massive amounts of salt are excreted. The magnitude of responses to loop diuretics is limited by both the existing salt and water balance and the delivery of drug to its site of action. Contraction of ECF volume lessens the response by enhancing proximal and distal tubular reabsorption of Na⁺. Renal insufficiency causes less drug to reach the NKCC2 transporter because glomeruli, proximal tubular pathways, or both, have been compromised.

The value of loop diuretics in pulmonary edema may be attributed in part to their stimulation of prostaglandin synthesis in kidney and lung. Furosemide and ethacrynic acid increase renal blood flow for brief intervals, promoting the urinary excretion of prostaglandin E. IV injection of furosemide also reduces pulmonary arterial pressure and peripheral venous compliance. Indomethacin, an inhibitor of prostaglandin synthesis (see Chapter 15), interferes with these actions.

Common indications for loop diuretics are listed in the Therapeutic Overview Box. Often, their use overlaps those of thiazides, with some major differences. For example, the greater efficacy of loop agents often evokes a diuresis in edemas that are cardiovascular, renal, or hepatic in origin. On the other hand, it has been reported that thiazides and related drugs, especially longer-acting agents, are more efficacious than loop agents in reducing blood pressure. Loop diuretics increase Ca⁺⁺ excretion and therefore are used to lower serum Ca⁺⁺ concentrations in patients with hypercalcemia. Loop diuretics also increase K⁺ excretion and are useful in treating acute and chronic hyperkalemia.

Potassium-Sparing Diuretics

Spironolactone and eplerenone are most effective in patients with primary hyperaldosteronism (adrenal adenoma or bilateral adrenal hyperplasia) or secondary hyperaldosteronism (congestive heart failure, cirrhosis, nephrotic syndrome). These drugs prevent binding of aldosterone to a cytosolic receptor in principal cells of the collecting tubule. They are also used to correct hypokalemia. These drugs can also be added to drug regimens, including thiazide, or loop diuretics, to further reduce ECF volume and prevent hypokalemia. They are especially appropriate for treatment of cirrhosis with ascites, a condition associated with secondary hyperaldosteronism. This class is as effective, if not more so, than loop or thiazide diuretics in this setting, because thiazide and loop diuretics are highly protein bound and enter the tubular fluid primarily by proximal tubular secretion. Tubular secretion of these agents in patients with cirrhosis and ascites decreases as a result of competition with toxic organic metabolites. Because thiazide and loop diuretics act at the apical cell membrane, decreased tubular secretion and lower concentrations inside the tubules reduce their effectiveness. Inhibitors of aldosterone, on the other hand, do not depend on filtration or secretion, because they gain access to their receptors from the blood side. A combination of a loop diuretic with spironolactone can be used to increase natriuresis when the diuretic effect of an aldosterone inhibitor alone is inadequate.

Although their natriuretic action is weak, these agents lower blood pressure in patients with mild or moderate hypertension and are often prescribed for this purpose. Recent trials suggest reduction in morbidity and mortality associated with addition of spironolactone to standard treatment of heart failure.

Triamterene and amiloride are generally used in combination with K⁺-wasting diuretics, especially when it is clinically important to maintain normal serum K⁺ (e.g., patients with dysrhythmias, receiving a cardiac glycoside, or with low serum K⁺). Fixed-combination preparations are generally not appropriate for initial therapy but may be more expedient once the dosage is demonstrated to be correct. Because the site and mechanism of action of these drugs differ from those of thiazides and loop agents, they are sometimes administered together to increase the response in patients who are refractory to a single drug.

Diuretic Resistance

During therapy with a loop diuretic, a patient may no longer respond to a previously effective dose. Chronic use of loop diuretics is associated with an adaptive response by nephron segments distal to their site of action. Distal tubule cells after chronic loop diuretic administration are characterized by cellular hypertrophy, hyperplasia, increased activity, and expression of Na⁺/Cl⁻cotransporter and increased Na⁺/K⁺-ATPase activity. This adaptation is thought to be due to higher rates of solute delivery to distal nephron segments and to an increase in aldosterone. The net result is a reduction of natriuresis normally expected from loop diuretic administration, due to a compensatory increase in Na⁺ reabsorption by distal tubule cells. Combined use of a loop and a thiazide diuretic counteracts the adaptive response after chronic diuretic use.

Additional factors may contribute to resistance, including a high NaCl intake, progressive renal failure, concomitant use of a nonsteroidal antiinflammatory agent, reduced GI absorption stemming from edema of the bowel, or hypoalbuminemia and albuminuria. Solutions include combined use of a loop and another diuretic, especially a thiazide.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Repeated use of diuretics is frequently associated with shifts in acid-base balance and changes in serum electrolytes. Shifts frequently encountered in patients on continuous diuretic therapy include K⁺ depletion and hyperuricemia. Patients at risk include the elderly, those with severe disease, those taking cardiac glycosides, and the malnourished. Such changes are difficult to avoid in most patients unless counteractive measures are taken. Supplemental intake of K⁺ (dietary or oral KCl) or concomitant use of K⁺-sparing with thiazide or loop diuretics is often used to circumvent this problem.

Paradoxical diuretic-induced edema may occur in patients with hypertension, if diuretics are abruptly withdrawn after long-term use. This occurs because long-term use results in a persistently elevated plasma renin activity and a secondary aldosteronism. If it is necessary to discontinue diuretic therapy, a stepwise reduction over a few weeks combined with a reduction in Na⁺ intake is recommended. The main problems are summarized in the Clinical Problems Box.

Osmotic Diuretics

Acute expansion of ECF volume engendered by osmotic diuretics increases the workload of the heart. Patients in cardiac failure are especially susceptible, and pulmonary edema may develop. Therefore they should not be treated with these drugs. Underlying heart disease in the absence of frank congestive heart failure, though not an absolute contraindication, is a serious risk factor. Mannitol is sometimes given to restore urine flow in patients in oliguric or anuric states induced by extrarenal factors (e.g., hypovolemia, hypotension). In these cases the response to a test dose should be evaluated before therapeutic quantities are administered.

Severe volume depletion and hypernatremia may result from prolonged administration of mannitol unless Na⁺ and water losses are replaced. Mild hyperkalemia is often observed, but intolerable K⁺ elevations are not likely, except in patients with diabetes, adrenal insufficiency, or severely impaired renal function.

Carbonic Anhydrase Inhibitors

Among the side effects of carbonic anhydrase inhibitors are metabolic acidosis, drowsiness, fatigue, central nervous system depression, and paresthesia. Hypersensitivity reactions are rare.

Thiazide Diuretics

Thiazides (and loop diuretics), whose action is exerted proximal to the K⁺ secretory sites, increase the excretion of K⁺. The fraction of patients in whom hypokalemia develops or who show evidence of K⁺ depletion while undergoing long-term treatment is variable. Some younger people with hypertension may have no effect or become only slightly hypokalemic. A clinical trial showed no difference in mortalities and cardiac-related events between hypertensive patients taking thiazides and patients treated with β adrenergic receptor-blocking drugs. Mild hypokalemia should be avoided in cirrhotic patients, those taking cardiac glycosides, diabetics, and the elderly. Disturbances in insulin and glucose metabolism can often be prevented, if K⁺ depletion is avoided.

Although Mg⁺⁺ is primarily reabsorbed in the proximal tubule, thiazides and loop diuretics can accelerate its excretion. Mg⁺⁺ depletion in patients on long-term diuretic therapy is occasionally reported and is considered by some to be a risk factor for ventricular dysrhythmias. Addition of K⁺-sparing diuretics reportedly prevents Mg⁺⁺ loss.

Thiazides increase the serum concentration of urate by increasing proximal tubular reabsorption and reducing tubular secretion. Hyperuricemia develops in more than 50% of patients on long-term thiazide therapy. In most, the elevation is modest and does not precipitate gout, unless the patient has primary disease or a gouty diathesis. Currently, there is no reason to believe that the risk of hyperuricemia outweighs the benefits of thiazide therapy in most patients.

Thiazide diuretics produce clinically significant reductions in plasma Na⁺ (hyponatremia) in some patients. Although the magnitude of the hyponatremia is variable, values of less than 100 mEq/L have been reported, which can be life-threatening.

Long-term treatment with thiazide diuretics could result in small increases in serum lipid and lipoprotein concentrations. Low-density lipoprotein-cholesterol and triglyceride concentrations may increase during short-term therapy, but total cholesterol and triglyceride concentrations usually return to baseline values in studies of more than 1 year. This action may be linked to glucose intolerance and may be a consequence of K⁺ depletion.

Because most complications of thiazide therapy are direct manifestations of their pharmacological effects, adverse events are usually predictable. However, many adverse reactions have no apparent relationship to the known pharmacology of the drugs (see Clinical Problems Box). Although relatively uncommon, these hazards are usually more serious. Thiazides also reduce the clearance of lithium, and as a rule should not be administered concomitantly. Although not absolutely contraindicated, their use in pregnant women is not recommended unless the anticipated benefit justifies the risk. Thiazides cross the placenta and appear in breast milk. Anuria and a known hypersensitivity to sulfonamides are absolute contraindications.

Loop Diuretics

Loop diuretics also increase excretion of K⁺, Ca⁺⁺, Mg⁺⁺, and H⁺, and their use is associated with all the electrolyte depletion phenomena associated with thiazide use. Similarly, carbohydrate intolerance and hyperlipidemia have also been observed.

Vertigo and deafness sometimes develop in patients receiving large IV doses of loop diuretics; the coadministration of an aminoglycoside antibiotic produces additive effects. Higher rates of ototoxicity are associated with ethancrynic acid, limiting its use. Additional drug interactions occur with indomethacin (decreased activity), warfarin (displacement from plasma protein), and lithium (decreased clearance and increased risk of toxicity). All diuretics are contraindicated in anuric patients.

Potassium-Sparing Diuretics

The most serious adverse effect of spironolactone therapy is hyperkalemia. Serum K⁺ should be monitored periodically even when the drug is administered with a K⁺-wasting diuretic. Gynecomastia may occur in men, possibly as a consequence of the binding of canrenone to androgen receptors. Decreased libido and impotence have been reported. Menstrual irregularities, hirsutism, or swelling and breast tenderness may develop in women. Triamterene and amiloride may cause hyperkalemia, even when a K⁺-wasting diuretic is part of the therapy. The risk

CLINICAL PROBLEMS

Osmotic Diuretics

Acute increase in ECF volume and serum K⁺ concentration, nausea and vomiting, headache

Carbonic Anhydrase Inhibitors

Metabolic acidosis, drowsiness, fatigue, central nervous system depression, paresthesia

Thiazides

Depletion phenomena (hypokalemia, dilutional hyponatremia, hypochloremic alkalosis, hypomagnesemia), retention phenomena (hyperuricemia, hypercalcemia), metabolic changes (hyperglycemia, hyperlipidemia, insulin resistance), hypersensitivity (fever, rash, purpura, anaphylaxis), and azotemia in patients with poor renal function.

Loop Diuretics

Hypokalemia; hyperuricemia; metabolic alkalosis; hyponatremia; hearing deficits, particularly with ethacrynic acid; watery diarrhea with ethacrynic acid

K⁺-sparing Diuretics

Aldosterone inhibitors: hyperkalemia, gynecomastia, hirsutism, menstrual irregularities

Triamterene: hyperkalemia, megaloblastic anemia in patients with cirrhosis

Amiloride: hyperkalemia, increase in blood urea nitrogen, glucose intolerance in diabetes mellitus

is highest in patients with limited renal function. Additional complications include elevated serum blood urea nitrogen and uric acid, glucose intolerance, and GI tract disturbances. Triamterene may contribute to, or initiate, formation of renal stones, and hypersensitivity reactions may occur in patients receiving it. Some drug-drug interactions involving diuretics are presented in Table 21-4.

TABLE 21–4 Potential Drug Interactions

Diuretic	Drug Class or Agent	Problem
Thiazide diuretics	β Adrenergic blockers	Increase in blood glucose, urates, and lipids
Thiazide diuretics	Chlorpropamide	Hyponatremia
Thiazides and loop diuretics	Digitalis glycosides	Hypokalemia resulting in increased digitalis binding and toxicity
Thiazides and loop diuretics	Adrenal steroids	Enhanced hypokalemia
Loop diuretics	Aminoglycosides	Ototoxicity, nephrotoxicity
K⁺-sparing diuretics	Angiotensin-converting enzyme inhibitors	Hyperkalemia, cardiac effects

New Horizons

Novel diuretics that can antagonize water transport are currently in development or clinical trials. There are two ways to block water transport:

• Antagonize the action of vasopressin with selective V₂-vasopressin receptor antagonists.

• Antagonize renal epithelial water channels.

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Osmotic Diuretics

Isosorbide dinitrate (Dilitrate-SR, Isochron)

Mannitol (Osmitrol)

Carbonic Anhydrase Inhibitors

Acetazolamide (Diamox)

Methazolamide (Neptazane)

Loop Diuretics, Types I and II

Bumetanide (Bumex)

Ethacrynic acid (Edecrin)

Furosemide (Lasix)

Torsemide (Demadex)

K⁺-sparing Diuretics

Amiloride hydrochloride (Midamor)

Eplerenone (Inspra)

Spironolactone (Aldactone)

Triamterene (Dyrenium)

Others

Nesiritide (Natrecor)

Quinethazone (Hydromox)

The use of a vasopressin V₂ receptor antagonist has been shown to be effective in inducing water diuresis in animals. Such an effect in humans could be advantageous in treatment of disorders in which water excretion is low as a result of high vasopressin concentrations. Congestive heart failure, cirrhosis, and nephrotic syndrome are conditions characterized by ECF volume expansion resulting from NaCl and water retention. A decrease in cardiac output (congestive heart failure) or in effective arterial volume (cirrhosis, nephrotic syndrome) stimulate vasopressin release and reduce water excretion. The effect of the excess vasopressin on collecting tubule cells leads to hyponatremia. Antagonism of V₂ receptors in such circumstances could facilitate water excretion. Also, treatment of patients with chronic hyponatremia caused by inappropriate antidiuretic hormone secretion could be facilitated with a selective V₂ receptor antagonist.

Alternatively, water excretion could be enhanced through use of agents that inhibit water channels. Our understanding of membrane water transport has advanced significantly with the molecular characterization of a new family of water transport proteins, referred to as aquaporins. The first water channel identified was aquaporin-1. This channel, which is constitutively active, was cloned after its purification from red blood cell membranes. Of the 10 aquaporins identified, at least 7 are expressed in kidney. Aquaporin-1 is expressed at high levels in the proximal tubule and descending limb, and its high expression level correlates with the high water permeability in these nephron segments. Aquaporin-2 is abundantly expressed in the principal cells of the collecting duct and regulates water reabsorption in response to vasopressin. Recent studies indicate that it is involved in several inherited and acquired disorders of water balance, such as inherited and acquired forms of nephrogenic diabetes insipidus. Aquaporins-3 and -4 are expressed on the basolateral membranes of collecting duct cells and allow water to exit the cells after its absorption from the apical membrane. Although expressed in kidneys, less is known about other aquaporins. The development of drugs that selectively antagonize aquaporins-1 or -2, which would in turn lead to selective inhibition of water transport in proximal or distal tubules, could lead to therapeutic intervention in disorders of water balance.

Recent clinical studies have targeted the natriuretic peptide family in mediating natriuresis in disorders of heart failure (see Chapter 23). The renal hemodynamic effects of A and B natriuretic peptides include increased GFR, afferent arteriolar dilation, and efferent arteriolar constriction. In addition, they have direct effects to block Na⁺ transport in the inner medullary collecting duct and block aldosterone release. Nesiritide, a recombinant human B natriuretic peptide, is currently used for the treatment of fluid retention in congestive heart failure.