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  3. Section V - Drugs Affecting Renal and Cardiovascular Function

Section V - Drugs Affecting Renal and Cardiovascular Function

Diuretics increase the rate of urine flow and sodium excretion and are used to adjust the volume and/or composition of body fluids in a variety of clinical situations, including hypertension, heart failure, renal failure, nephrotic syndrome, and cirrhosis. The objective of this chapter is to provide the reader with unifying concepts as to how the kidney operates and how diuretics modify renal function. The chapter begins with a description of renal anatomy and physiology, as this information is

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  1. Section V. Drugs Affecting Renal and Cardiovascular Function Chapter 29. Diuretics Overview Diuretics increase the rate of urine flow and sodium excretion and are used to adjust the volume and/or composition of body fluids in a variety of clinical situations, including hypertension, heart failure, renal failure, nephrotic syndrome, and cirrhosis. The objective of this chapter is to provide the reader with unifying concepts as to how the kidney operates and how diuretics modify renal function. The chapter begins with a description of renal anatomy and physiology, as this information is prerequisite to a discussion of diuretic pharmacology. Categories of diuretics are introduced and then described with regard to chemistry, mechanism of action, site of action, effects on urinary composition, and effects on renal hemodynamics. Near the end of the chapter, diuretic pharmacology is integrated with a discussion of mechanisms of edema formation and the role of diuretics in clinical medicine. Therapeutic applications of diuretics are expanded upon in Chapters 33: Antihypertensive Agents and the Drug Therapy of Hypertension (hypertension) and 34: Pharmacological Treatment of Heart Failure (heart failure). Renal Anatomy and Physiology Renal Anatomy The main renal artery branches close to the renal hilum into segmental arteries, which, in turn, subdivide to form interlobar arteries that pierce the renal parenchyma. The interlobar arteries curve at the border of the renal medulla and cortex to form arc-like vessels known as arcuate arteries. Arcuate arteries give rise to perpendicular branches, called interlobular arteries, which enter the renal cortex and supply blood to the afferent arterioles. A single afferent arteriole penetrates the glomerulus of each nephron and branches extensively to form the glomerular capillary nexus. These branches coalesce to form the efferent arteriole. Efferent arterioles of superficial glomeruli ascend toward the kidney surface before splitting into peritubular capillaries that service the tubular elements of the renal cortex. Efferent arterioles of juxtamedullary glomeruli descend into the medulla and divide to form the descending vasa recta, which supply blood to the capillaries of the medulla. Blood returning from the medulla via the ascending vasa recta drains directly into the arcuate veins, and blood from the peritubular capillaries of the cortex enters the interlobular veins, which, in turn, connect with the arcuate veins. Arcuate veins drain into interlobar veins, which in turn drain into segmental veins, and blood leaves the kidney via the main renal vein. The basic urine-forming unit of the kidney is the nephron, which consists of a filtering apparatus, the glomerulus, connected to a long tubular portion that reabsorbs and conditions the glomerular ultrafiltrate. Each human kidney is composed of approximately 1 million nephrons. The nomenclature for segments of the tubular portion of the nephron has become increasingly complex as renal physiologists have subdivided the nephron into shorter and shorter named segments. These subdivisions initially were based on the axial location of the segments but increasingly have been based on the morphology of the epithelial cells lining the various nephron segments. Figure 29–1 illustrates the currently accepted subdivision of the nephron into 14 subsegments. Commonly encountered names that refer to these subsegments and to combinations of subsegments are
  2. included. Figure 29–1. Anatomy and Nomenclature of the Nephron.
  3. Glomerular Filtration In the glomerular capillaries, a portion of the plasma water is forced through a filter that has three basic components: the fenestrated capillary endothelial cells, a basement membrane lying just beneath the endothelial cells, and the filtration slit diaphragms formed by the epithelial cells that cover the basement membrane on its urinary space side. Solutes of small size flow with filtered water (solvent drag) into the urinary (Bowman's) space, whereas formed elements and macromolecules are retained by the filtration barrier. For each nephron unit, the rate of filtration (single-nephron glomerular filtration rate, SNGFR) is a function of the hydrostatic pressure in the glomerular capillaries (PGC), the hydrostatic pressure in Bowman's space (which can be equated with pressure in the proximal tubule, PT), the mean colloid osmotic pressure in the glomerular capillaries ( GC), the colloid osmotic pressure in the proximal tubule ( T), and the ultrafiltration coefficient (Kf), according to the equation: SNGFR = Kf[(PGC– ( – )] (29–1) GC T If PGC–PT is defined as the transcapillary hydraulic pressure difference ( P), and if is negligible T (as it usually is since little protein is filtered), then: SNGFR = Kf( P– ) (29–2) GC This latter equation succinctly expresses the three major determinants of SNGFR. However, each of these three determinants can be influenced by a number of other variables. Kf is determined by the physicochemical properties of the filtering membrane and by the surface area available for filtration. P is determined primarily by the arterial blood pressure and by the proportion of the arterial pressure that is transmitted to the glomerular capillaries. This is governed by the relative resistances of preglomerular and postglomerular vessels. GC is determined by two variables, i.e., the concentration of protein in the arterial blood entering the glomerulus and the single-nephron blood flow (QA). QA influences GC because, as blood transverses the glomerular capillary bed, filtration concentrates proteins in the capillaries, causing GC to rise with distance along the glomerular bed. When QA is high, this effect is reduced; however, when QA is low, GC may increase to the point that GC= P and filtration ceases (a condition known as filtration equilibrium; seeDeen et al., 1972). Overview of Nephron Function Approximately 120 ml of ultrafiltrate is formed each minute, yet only 1 ml/min of urine is produced. Therefore, greater than 99% of the glomerular ultrafiltrate is reabsorbed at a staggering energy cost. The kidneys consume 7% of total-body oxygen intake despite the fact that the kidneys make up only 0.5% of body weight. The kidney is designed to filter large quantities of plasma, reabsorb those substances that the body must conserve, and leave behind and/or secrete substances that must be eliminated. The proximal tubule is contiguous with Bowman's capsule and takes a tortuous path until finally forming a straight portion that dives into the renal medulla. The proximal tubule has been subdivided into S1, S2, and S3 segments based on the morphology of the epithelial cells lining the tubule. Normally, approximately 65% of filtered Na+ is reabsorbed in the proximal tubule, and since this part of the tubule is highly permeable to water, reabsorption is essentially isotonic. Between the outer and inner strips of the outer medulla, the tubule abruptly changes morphology to
  4. become the descending thin limb (DTL), which penetrates the inner medulla, makes a hairpin turn, and then forms the ascending thin limb (ATL). At the juncture between the inner and outer medulla, the tubule once again changes morphology and becomes the thick ascending limb, which is made up of three segments: a medullary portion (MTAL), a cortical portion (CTAL), and a postmacular segment. Together, the proximal straight tubule, DTL, ATL, MTAL, CTAL, and postmacular segment are known as the loop of Henle. The DTL is highly permeable to water, yet its permeability to NaCl and urea is low. In contrast, the ATL is permeable to NaCl and urea but is impermeable to water. The thick ascending limb actively reabsorbs NaCl but is impermeable to water and urea. Approximately 25% of filtered Na+ is reabsorbed in the loop of Henle, mostly in the thick ascending limb, which has a large reabsorptive capacity. The thick ascending limb passes between the afferent and efferent arterioles and makes contact with the afferent arteriole via a cluster of specialized columnar epithelial cells known as the macula densa. The macula densa is strategically located to sense concentrations of NaCl leaving the loop of Henle. If the concentration of NaCl is too high, the macula densa sends a chemical signal (perhaps adenosine) to the afferent arteriole of the same nephron, causing it to constrict. This in turn causes a reduction in PGC and QA and decreases SNGFR. This homeostatic mechanism, known as tubuloglomerular feedback (TGF), serves to protect the organism from salt and volume wasting. Besides causing a TGF response, the macula densa also regulates renin release from the adjacent juxtaglomerular cells in the wall of the afferent arteriole. Approximately 0.2 mm past the macula densa, the tubule changes morphology once again to become the distal convoluted tubule (DCT). The postmacular segment of the thick ascending limb and the distal convoluted tubule often are referred to as the early distal tubule. Like the thick ascending limb, the DCT actively transports NaCl and is impermeable to water. Since these characteristics impart the ability to produce a dilute urine, the thick ascending limb and the DCT are collectively called the diluting segment of the nephron, and the tubular fluid in the DCT is hypotonic regardless of hydration status. However, unlike the thick ascending limb, the DCT does not contribute to the countercurrent-induced hypertonicity of the medullary interstitium (see below). The collecting duct system (connecting tubule + initial collecting tubule + cortical collecting duct + outer and inner medullary collecting duct) is an area of fine control of ultrafiltrate composition and volume. It is here that final adjustments in electrolyte composition are made, a process modulated by the adrenal steroid, aldosterone. In addition, permeability of this part of the nephron to water is modulated by antidiuretic hormone (ADH; seeChapter 30: Vasopressin and Other Agents Affecting the Renal Conservation of Water). The more distal portions of the collecting duct pass through the renal medulla, where the interstitial fluid is markedly hypertonic. In the absence of ADH, the collecting duct system is impermeable to water, and a dilute urine is excreted. However, in the presence of ADH, the collecting duct system is permeable to water, so that water is reabsorbed. The movement of water out of the tubule is driven by the steep concentration gradient that exists between the tubular fluid and the medullary interstitium. The hypertonicity of the medullary interstitium plays a vital role in the ability of mammals and birds to concentrate urine and is therefore a key adaptation necessary for living in a terrestrial environment. This is accomplished via a combination of the unique topography of the loop of Henle and the specialized permeability features of the loop's subsegments. Although the precise mechanism giving rise to the medullary hypertonicity has remained elusive, the passive countercurrent multiplier hypothesis of Kokko and Rector (1972) is an intuitively attractive model
  5. that is qualitatively accurate (seeSands and Kokko, 1996). According to this hypothesis, the process begins with active transport in the thick ascending limb, which concentrates NaCl in the interstitium of the outer medulla. Since this segment of the nephron is impermeable to water, active transport in the ascending limb dilutes the tubular fluid. As the dilute fluid passes into the collecting duct system, water is extracted if and only if ADH is present. Since the cortical and outer medullary collecting ducts have a low permeability to urea, urea is concentrated in the tubular fluid. The inner medullary collecting duct, however, is permeable to urea, so that urea diffuses into the inner medulla where it is trapped by countercurrent exchange in the vasa recta. Since the DTL is impermeable to salt and urea, the high urea concentration in the inner medulla extracts water from the DTL and concentrates NaCl in the tubular fluid of the DTL. As the tubular fluid enters the ATL, NaCl diffuses out of the salt-permeable ATL, thus contributing to the hypertonicity of the medullary interstitium. General Mechanism of Renal Epithelial Transport Figure 29–2 illustrates seven mechanisms by which solute crosses renal epithelial cell membranes. If bulk water flow occurs across a membrane, solute molecules will be transferred by convection across the membrane, a process known as solvent drag. Solutes with sufficient lipid solubility may also dissolve in the membrane and diffuse across the membrane down their electrochemical gradients (simple diffusion). Many solutes, however, have limited lipid solubility, and transport must rely on integral proteins embedded in the cell membrane. In some cases, the integral protein merely provides a conductive pathway (pore) through which the solute may diffuse passively (channel-mediated diffusion). In other cases, the solute may bind to the integral protein and, due to a conformational change in the protein, be transferred across the cell membrane down an electrochemical gradient (carrier-mediated or facilitated diffusion, also called uniport). However, this process will not result in net movement of solute against an electrochemical gradient. If solute must be moved "uphill" against an electrochemical gradient, then either primary active transport or secondary active transport is required. With primary active transport, ATP hydrolysis is coupled directly to conformational changes in the integral protein, thus providing the necessary free energy (ATP-mediated transport). Often, ATP-mediated transport is used to create an electrochemical gradient for a given solute, and the free energy of that solute gradient is then released to drive the "uphill" transport of other solutes. This process requires symport (cotransport of solute species in the same direction) or antiport (countertransport of solute species in opposite directions) and is known as secondary active transport. Figure 29–2. Seven Basic Mechanisms for Transmembrane Transport of Solutes. 1, convective flow in which dissolved solutes are "dragged" by bulk water flow; 2, simple diffusion of lipophilic solute across membrane; 3, diffusion of solute through pore; 4, transport of solute by carrier protein down electrochemical gradient; 5, transport of solute by carrier protein against electrochemical gradient with ATP hydrolysis providing driving force; 6 and 7, cotransport and countertransport, respectively, of solutes with one solute traveling "uphill" against an electrochemical gradient and the other solute traveling down an electrochemical gradient.
  6. The kinds of transport achieved in a particular nephron segment depend mainly on which transporters are present and whether they are embedded in the luminal or basolateral membrane. A general model of renal tubular transport is shown in Figure 29–3 and can be summarized as follows: Figure 29–3. Generic Mechanism of Renal Epithelial Cell Transport (See Text for Details). S, symporter; A, antiporter; CH, ion channel; WP, water pore; U, uniporter; ATPase, Na+,K+–ATPase (sodium pump); X and Y, transported solutes; P, membrane-permeable (reabsorbable) solutes; I, membrane-impermeable (nonreabsorbable) solutes; PD, potential difference across indicated membrane or cell.
  7. 1. Na+,K+–ATPase (sodium pump) in the basolateral membrane hydrolyzes ATP, which results in the transport of Na+ into the intercellular and interstitial spaces and the movement of K+ into the cell. Although other ATPases exist in selected renal epithelial cells and participate in the transport of specific solutes (e.g., Ca2+–ATPase and H+–ATPase), the bulk of all transport in the kidney is due to the abundant supply of Na+,K+–ATPase in the basolateral membranes of the renal epithelial cells. 2. Na+ may diffuse across the luminal membrane via Na+ channels into the epithelial cell down the
  8. electrochemical gradient for Na+ that is established by the basolateral Na+,K+–ATPases. In addition, the free energy available in the electrochemical gradient for Na+ is tapped by integral proteins in the luminal membrane, resulting in cotransport of various solutes against their electrochemical gradients by symporters (e.g., Na+–glucose, Na+–Pi, Na+–amino acid). This process results in movement of Na+ and cotransported solutes out of the tubular lumen into the cell. Also, antiporters (e.g., Na+–H+) countertransport Na+ out of and some solutes into the tubular lumen. 3. Na+ exits the basolateral membrane into the intercellular and interstitial spaces via the Na+ pump or via symporters or antiporters in the basolateral membrane. 4. The action of Na+-linked symporters in the luminal membrane causes the concentration of substrates for these symporters to rise in the epithelial cell. These electrochemical gradients then permit simple diffusion or mediated transport (symporters, antiporters, uniporters, and channels) of solutes into the intercellular and interstitial spaces. 5. Accumulation of Na+ and other solutes in the intercellular space creates a small osmotic pressure differential across the epithelial cell. In water-permeable epithelium, water moves into the intercellular spaces driven by the osmotic pressure differential. Water moves through aqueous pores in both the luminal and the basolateral cell membranes as well as through the tight junctions (paracellular pathway). Bulk water flow carries some solutes into the intercellular space by solvent drag. 6. Movement of water into the intercellular space concentrates other solutes in the tubular fluid, resulting in an electrochemical gradient for these substances across the epithelium. Membrane- permeable solutes then move down their electrochemical gradients into the intercellular space via both the transcellular (simple diffusion, symporters, antiporters, uniporters, and channels) and paracellular pathways. Membrane-impermeable solutes remain in the tubular lumen and are excreted in the urine with an obligatory amount of water. 7. As water and solutes accumulate in the intercellular space, the hydrostatic pressure increases, thus providing a driving force for bulk water flow. Bulk water flow carries solute (solute convection) out of the intercellular space into the interstitial space and, finally, into the peritubular capillaries. The movement of fluid into the peritubular capillaries is governed by the same Starling forces that determine transcapillary fluid movement for any capillary bed. Mechanism of Organic Acid and Organic Base Secretion The kidney is a major organ involved in the elimination of organic chemicals from the body. Organic molecules may enter the renal tubules by glomerular filtration of molecules not bound to plasma proteins or may be actively secreted directly into the tubules. The proximal tubule has a highly efficient transport system for organic acids and an equally efficient but separate transport system for organic bases. Current models for these secretory systems are illustrated in Figure 29–4. Both systems are powered by the sodium pump in the basolateral membrane, involve secondary and tertiary active transport, and utilize a poorly characterized facilitated-diffusion step. The antiporter that exchanges -ketoglutarate for organic acids has been cloned from several species, including human beings (Lu et al., 1999). The optimal substrate for transport by the organic acid secretory mechanism is a molecule with a negative or partial negative charge, separated by 6 to 7 Å from a second negative charge, and a hydrophobic region 8 to 10 Å long. However, much flexibility exists around this optimal motif, and the system transports a large variety of organic acids. The organic base secretory mechanism is even less discriminating and may involve a family of related transport mechanisms. This system(s) transports many drugs containing an amine nitrogen positively charged at physiological pH.
  9. Figure 29–4. Mechanisms of Organic Acid (A) and Organic Base (B) Secretion in the Proximal Tubule. The numbers 1, 2, and 3 refer to primary, secondary, and tertiary active transport. A–, organic acid (anion); C+, organic base (cation); KG2–, -ketoglutarate, but also other dicarboxylates. Renal Handling of Specific Anions and Cations Reabsorption of Cl– generally follows reabsorption of Na+. In segments of the tubule with low- resistance tight junctions (i.e., "leaky" epithelium), such as the proximal tubule and thick ascending limb, Cl– movement can occur paracellularly. With regard to transcellular Cl– flux, Cl– crosses the luminal membrane via antiport with formate and oxalate (proximal tubule), symport with Na+/K+
  10. (thick ascending limb), symport with Na+ (DCT), and antiport with HCO3– (collecting duct system). Cl– crosses the basolateral membrane via symport with K+ (proximal tubule and thick ascending limb), antiport with Na+/HCO3– (proximal tubule), and Cl– channels (thick ascending limb, DCT, collecting duct system). Eighty to ninety percent of filtered K+ is reabsorbed in the proximal tubule (diffusion and solvent drag) and thick ascending limb (diffusion), largely via the paracellular pathway. In contrast, the DCT and collecting duct system secrete variable amounts of K+via a conductive (channel-mediated) pathway. Modulation of the rate of K+ secretion in the collecting duct system, particularly by aldosterone, allows urinary excretion of K+ to be matched with dietary intake. The transepithelial potential difference (VT), lumen-positive in the thick ascending limb and lumen-negative in the collecting duct system, provides an important driving force for K+ reabsorption and secretion, respectively. Most of the filtered Ca2+ (approximately 70%) is reabsorbed by the proximal tubule by passive diffusion, probably via a paracellular route. Another 25% of filtered Ca2+ is reabsorbed by the thick ascending limb, mostly via a paracellular route driven by the lumen-positive VT, although a component of active Ca2+ reabsorption also may exist. The remaining Ca2+ is reabsorbed in the distal convoluted tubule and the connecting tubule via a transcellular pathway that is modulated by parathyroid hormone (PTH; seeChapter 62: Agents Affecting Calcification and Bone Turnover: Calcium, Phosphate, Parathyroid Hormone, Vitamin D, Calcitonin, and Other Compounds). PTH appears to increase Ca2+ channels in the luminal membrane, thereby facilitating the passive movement of Ca2+ into the epithelial cell. Ca2+ is extruded across the basolateral membrane by a Ca2+–ATPase and via Na+–Ca2+ antiport. Inorganic phosphate (Pi) is largely reabsorbed (80% of filtered load) by the proximal tubule. A Na+– Pi symporter uses the free energy of the Na+ electrochemical gradient to effect secondary active transport of Pi into the cell. The Na+–Pi symporter is inhibited by PTH. Pi exits the basolateral membrane down its electrochemical gradient by a poorly understood transport system. Only 20% to 25% of Mg2+ is reabsorbed in the proximal tubule, and only 5% is reabsorbed by the DCT and collecting duct system. The bulk of Mg2+ is reabsorbed in the thick ascending limb via a paracellular pathway driven by the lumen-positive VT. However, transcellular movement of Mg2+ also may occur with basolateral exit via Na+–Mg2+ antiport or via a Mg2+–ATPase. The renal tubules play an extremely important role in the reabsorption of HCO3– and secretion of protons (tubular acidification) and thus participate critically in the maintenance of acid–base balance. A description of these processes is presented in the section on carbonic anhydrase inhibitors. Principles of Diuretic Action By definition, diuretics are drugs that increase the rate of urine flow; however, clinically useful diuretics also increase the rate of excretion of Na+ (natriuresis) and of an accompanying anion, usually Cl–. NaCl in the body is the major determinant of extracellular fluid volume, and most clinical applications of diuretics are directed toward reducing extracellular fluid volume by decreasing total-body NaCl content. A sustained imbalance between dietary Na+ intake and Na+ loss is incompatible with life. A sustained positive Na+ balance would result in volume overload with pulmonary edema, and a sustained negative Na+ balance would result in volume depletion and cardiovascular collapse. Although continued administration of a diuretic causes a sustained net
  11. deficit in total-body Na+, the time course of natriuresis is finite as renal compensatory mechanisms bring Na+ excretion in line with Na+ intake, a phenomenon known as "diuretic braking." These compensatory, or braking, mechanisms include activation of the sympathetic nervous system, activation of the renin–angiotensin–aldosterone axis, decreased arterial blood pressure (which reduces pressure-natriuresis), hypertrophy of renal epithelial cells, increased expression of renal epithelial transporters, and perhaps alterations in natriuretic hormones such as atrial natriuretic peptide. Historically, the classification of diuretics was based on a mosaic of ideas such as site of action (loop diuretics), efficacy (high-ceiling diuretics), chemical structure (thiazide diuretics), similarity of action with other diuretics (thiazide-like diuretics), effects on potassium excretion (potassium- sparing diuretics), etc. However, since the mechanism of action of each of the major classes of diuretics is now reasonably well understood, a classification scheme based on mechanism of action is now possible and is used in this chapter. Diuretics not only alter the excretion of Na+, but also may modify renal handling of other cations (e.g., K+, H+, Ca2+, and Mg2+), anions (e.g., Cl–, HCO3–, and H2PO4–), and uric acid. In addition, diuretics may indirectly alter renal hemodynamics. Table 29–1 gives a comparison of the general effects of the major classes of diuretics. Inhibitors of Carbonic Anhydrase Acetazolamide (DIAMOX) is the prototype of a class of agents that have limited usefulness as diuretics but have played a major role in the development of fundamental concepts of renal physiology and pharmacology. Chemistry When sulfanilamide was introduced as a chemotherapeutic agent, metabolic acidosis was recognized as a side effect. This observation led to in vitro and in vivo studies demonstrating that sulfanilamide is an inhibitor of carbonic anhydrase. Subsequently, an enormous number of sulfonamides were synthesized and tested for the ability to inhibit carbonic anhydrase; of these compounds, acetazolamide has been most extensively studied. Table 29–2 lists the chemical structures of the three carbonic anhydrase inhibitors currently available in the United States— acetazolamide, dichlorphenamide (DARANIDE), and methazolamide (NEPTAZANE). The common molecular motif of available carbonic anhydrase inhibitors is an unsubstituted sulfonamide moiety. Mechanism and Site of Action Proximal tubular epithelial cells are richly endowed with the zinc metalloenzyme carbonic anhydrase, which is found in the luminal and basolateral membranes (type IV carbonic anhydrase, an enzyme tethered to the membrane by a glycosylphosphatidylinositol linkage) as well as in the cytoplasm (type II carbonic anhydrase). Davenport and Wilhelmi (1941) were the first to discover this enzyme in the mammalian kidney, and subsequent studies revealed the key role played by carbonic anhydrase in NaHCO3 reabsorption and acid secretion (seeMaren, 1967 and 1980). In the proximal tubule, the free energy in the Na+ gradient established by the basolateral Na+ pump is used by a Na+–H+ antiporter (also referred to as a Na+–H+ exchanger or NHE) in the luminal membrane to transport H+ into the tubular lumen in exchange for Na+ (Figure 29–5). In the lumen, H+ reacts with filtered HCO3– to form H2CO3, which rapidly decomposes to CO2 and water in the presence of carbonic anhydrase in the brush border. Normally the reaction between CO2 and water
  12. occurs slowly, but carbonic anhydrase reversibly accelerates this reaction several thousandfold. CO 2 is lipophilic and rapidly diffuses across the luminal membrane into the epithelial cell where it reacts with water to form H2CO3, a reaction catalyzed by cytoplasmic carbonic anhydrase. (The actual reaction catalyzed by carbonic anhydrase is OH–+ CO2 HCO3–; however, H2O OH–+ H+ and HCO3–+ H+ H2CO3, so that the net reaction is H2O + CO2 H2CO3.) Continued operation of the Na+–H+ antiporter maintains a low proton concentration in the cell, so that H2CO3 spontaneously ionizes to form H+ and HCO3–, creating an electrochemical gradient for HCO3– across the basolateral membrane. The electrochemical gradient for HCO3– is used by a Na+–HCO3– symporter (also called Na+–HCO3– cotransporter or NBC) in the basolateral membrane to transport NaHCO3 into the interstitial space. The net effect of this process is transport of NaHCO3 from the tubular lumen to the interstitial space followed by movement of water (isotonic reabsorption). Removal of water concentrates Cl– in the tubular lumen, and consequently Cl– diffuses down its concentration gradient into the interstitium via the paracellular pathway. Figure 29–5. NaHCO3 Reabsorption in Proximal Tubule and Mechanism of Diuretic Action of Carbonic Anhydrase (CA) Inhibitors. A, antiporter; S, symporter; CH, ion channel. (The actual reaction catalyzed by carbonic anhydrase is OH–+ CO2 HCO3–; however, H2O OH–+ H+, and HCO3–+ H+ H2CO3, so that the net reaction is H2O + CO2 H2CO3.) Numbers in parentheses indicate stoichiometry. Carbonic anhydrase inhibitors potently inhibit (IC50 for acetazolamide is 10 nM) both the membrane-bound and cytoplasmic forms of carbonic anhydrase, resulting in nearly complete abolition of NaHCO3 reabsorption in the proximal tubule (Cogan et al., 1979). Studies with a high- molecular-weight carbonic anhydrase inhibitor that only inhibits luminal enzyme because of limited cellular permeability indicate that inhibition of both the membrane-bound and cytoplasmic pools of carbonic anhydrase contributes to the diuretic activity of carbonic anhydrase inhibitors (Maren et al., 1997). Because of the large excess of carbonic anhydrase in proximal tubules, a high percentage
  13. of enzyme activity must be inhibited before an effect on electrolyte excretion is observed. Although the proximal tubule is the major site of action of carbonic anhydrase inhibitors, carbonic anhydrase also is involved in secretion of titratable acid in the collecting duct system (a process that involves a proton pump); therefore the collecting duct system is a secondary site of action for this class of drugs. Effects on Urinary Excretion Inhibition of carbonic anhydrase is associated with a rapid rise in urinary HCO 3– excretion to approximately 35% of filtered load. This, along with inhibition of titratable acid and ammonia secretion in the collecting duct system, results in an increase in urinary pH to approximately 8 and development of a metabolic acidosis. However, even with a high degree of inhibition of carbonic anhydrase, 65% of HCO3– is rescued from excretion by poorly understood mechanisms that may involve carbonic anhydrase–independent HCO3– reabsorption at downstream sites. Inhibition of the transport mechanism described in the preceding section results in increased delivery of Na+ and Cl– to the loop of Henle, which has a large reabsorptive capacity and captures most of the Cl– and a portion of the Na+. Thus, only a small increase in Cl– excretion occurs, HCO3– being the major anion excreted along with the cations Na+ and K+. The fractional excretion of Na+ may be as much as 5%, and the fractional excretion of K+ can be as much as 70%. The increased excretion of K+ is secondary to increased delivery of Na+ to the distal nephron. The mechanism by which increased distal delivery of Na+ enhances K+ excretion is described in the section on inhibitors of sodium channels. Carbonic anhydrase inhibitors also increase phosphate excretion (mechanism unknown), but have little or no effect on the excretion of Ca2+ or Mg2+. The effects of carbonic anhydrase inhibitors on renal excretion are self-limiting, probably because, as metabolic acidosis develops, the filtered load of HCO3– decreases to the point that the uncatalyzed reaction between CO2 and water is sufficient to achieve HCO3– reabsorption. Effects on Renal Hemodynamics By inhibiting proximal reabsorption, carbonic anhydrase inhibitors increase delivery of solutes to the macula densa. This triggers tubuloglomerular feedback (TGF), which increases afferent arteriolar resistance and reduces renal blood flow (RBF) and glomerular filtration rate (GFR) (Persson and Wright, 1982). Other Actions Carbonic anhydrase is present in a number of extrarenal tissues including the eye, gastric mucosa, pancreas, central nervous system (CNS), and red blood cells (RBCs). Carbonic anhydrase in the ciliary processes of the eye mediates the formation of large amounts of HCO 3– in aqueous humor. For this reason, inhibition of carbonic anhydrase decreases the rate of formation of aqueous humor and consequently reduces intraocular pressure. Acetazolamide frequently causes paresthesias and somnolence, suggesting an action of carbonic anhydrase inhibitors in the CNS. The efficacy of acetazolamide in epilepsy is in part due to the production of metabolic acidosis; however, direct actions of acetazolamide in the CNS also contribute to its anticonvulsant action. Due to interference with carbonic anhydrase activity in RBCs, carbonic anhydrase inhibitors increase CO 2 levels in peripheral tissues and decrease CO2 levels in expired gas. Large doses of carbonic anhydrase inhibitors reduce gastric acid secretion, but this has no therapeutic applications. Absorption and Elimination
  14. The oral bioavailability, plasma half-life, and route of elimination of the three currently available carbonic anhydrase inhibitors are listed in Table 29–2. Carbonic anhydrase inhibitors are avidly bound by carbonic anhydrase and, accordingly, tissues rich in this enzyme will have higher concentrations of carbonic anhydrase inhibitors following systemic administration. Toxicity, Adverse Effects, Contraindications, Drug Interactions Serious toxic reactions to carbonic anhydrase inhibitors are infrequent; however, these drugs are sulfonamide derivatives and, like other sulfonamides, may cause bone-marrow depression, skin toxicity, and sulfonamide-like renal lesions and may cause allergic reactions in patients hypersensitive to sulfonamides. With large doses, many patients exhibit drowsiness and paresthesias. Most adverse effects, contraindications, and drug interactions are secondary to urinary alkalinization or metabolic acidosis, including: (1) diversion of ammonia of renal origin from urine into the systemic circulation, a process that may induce hepatic encephalopathy (the drugs are contraindicated in patients with hepatic cirrhosis); (2) calculus formation and ureteral colic due to precipitation of calcium phosphate salts in an alkaline urine; (3) worsening of metabolic or respiratory acidosis (the drugs are contraindicated in patients with hyperchloremic acidosis or severe chronic obstructive pulmonary disease); (4) interference with the urinary tract antiseptic methenamine; and (5) reduction of the urinary excretion rate of weak organic bases. Therapeutic Uses Although acetazolamide is used for treatment of edema, the efficacy of carbonic anhydrase inhibitors as single agents is low, and carbonic anhydrase inhibitors are not widely employed in this regard. However, studies by Knauf and Mutschler (1997) indicate that the combination of acetazolamide with diuretics that block Na+ reabsorption at more distal sites in the nephron causes a marked natriuretic response in patients with low basal fractional excretion of Na+ (
  15. isosorbide, mannitol, and urea. Mechanism and Site of Action For many years it was thought that osmotic diuretics act primarily in the proximal tubule ( Wesson and Anslow, 1948). By acting as nonreabsorbable solutes, it was reasoned that osmotic diuretics limit the osmosis of water into the interstitial space and thereby reduce luminal Na+ concentration to the point that net Na+ reabsorption ceases. Indeed, early micropuncture studies supported this concept (Windhager et al., 1959). However, subsequent studies suggest that this mechanism, while operative, may be of only secondary importance. For instance, mannitol only slightly increases the delivery of Na+ and moderately increases the delivery of water out of the proximal tubule (Seely and Dirks, 1969), and urea does not alter proximal tubular reabsorption in rats at the time of a large osmotic diuresis (Kauker et al., 1970). Mannitol, on the other hand, markedly increases the delivery of Na+ and water out of the loop of Henle (Seely and Dirks, 1969), suggesting that the major site of action is the loop of Henle. By extracting water from intracellular compartments, osmotic diuretics expand the extracellular fluid volume, decrease blood viscosity, and inhibit renin release. These effects increase RBF, and the increase in renal medullary blood flow removes NaCl and urea from the renal medulla, thus reducing medullary tonicity. Also, under some circumstances, prostaglandins may contribute to the renal vasodilation and medullary washout induced by osmotic diuretics (Johnston et al., 1981). A reduction in medullary tonicity causes a decrease in the extraction of water from the DTL, which in turn limits the concentration of NaCl in the tubular fluid entering the ATL. This latter effect diminishes the passive reabsorption of NaCl in the ATL. In addition, the marked ability of osmotic diuretics to inhibit reabsorption of Mg2+, a cation that is mainly reabsorbed in the thick ascending limb, suggests that osmotic diuretics also interfere with transport processes in the thick ascending limb. The mechanism of this effect is unknown. In summary, osmotic diuretics act both in the proximal tubule and the loop of Henle, with the latter being the primary site of action. Also, osmotic diuretics probably act by an osmotic effect in the tubules and by reducing medullary tonicity. Effects on Urinary Excretion Osmotic diuretics increase the urinary excretion of nearly all electrolytes, including Na+, K+, Ca2+, Mg2+, Cl–, HCO3–, and phosphate. Effects on Renal Hemodynamics As indicated in the preceding section, osmotic diuretics increase RBF by a variety of mechanisms. Osmotic diuretics dilate the afferent arteriole, which increases PGC, and dilute the plasma, which decreases GC. These effects would increase GFR were it not for the fact that osmotic diuretics also increase PT. In general, superficial SNGFR is increased but total GFR is little changed. Absorption and Elimination The oral bioavailability, plasma half-life, and route of elimination of the four currently available osmotic diuretics are listed in Table 29–3. Glycerin and isosorbide can be given orally, whereas mannitol and urea must be administered intravenously.
  16. Toxicity, Adverse Effects, Contraindications, Drug Interactions Osmotic diuretics are distributed in the extracellular fluid and contribute to the extracellular osmolality. Thus, water is extracted from intracellular compartments, and the extracellular fluid volume becomes expanded. In patients with heart failure or pulmonary congestion, this may cause frank pulmonary edema. Extraction of water also causes hyponatremia, which may explain common adverse effects, including headache, nausea, and vomiting. On the other hand, loss of water in excess of electrolytes can cause hypernatremia and dehydration. In general, osmotic diuretics are contraindicated in patients who are anuric due to severe renal disease or who are unresponsive to test doses of the drugs. Urea may cause thrombosis or pain if extravasation occurs, and it should not be administered to patients with impaired liver function because of the risk of elevation of blood ammonia levels. Both mannitol and urea are contraindicated in patients with active cranial bleeding. Glycerin is metabolized and can cause hyperglycemia. Therapeutic Uses A rapid decrease in GFR, i.e., acute renal failure (ARF), is a serious medical condition that occurs in 5% of hospitalized patients and is associated with a significant mortality rate. ARF can be caused by diverse conditions both extrinsic (prerenal and postrenal failure) and intrinsic to the kidney. Acute tubular necrosis (ATN), i.e., damage to tubular epithelial cells, accounts for the majority of cases of intrinsic ARF. In animal models, mannitol is effective in attenuating the reduction in GFR associated with ATN when administered before the ischemic insult or offending nephrotoxin. The renal protection afforded by mannitol may be due to removal of obstructing tubular casts, dilution of nephrotoxic substances in the tubular fluid, and/or reduction of swelling of tubular elements via osmotic extraction of water. Although prophylactic mannitol is effective in animal models of ATN, the clinical efficacy of mannitol is less well established. Most published clinical studies have been uncontrolled, and controlled studies have not shown a benefit over hydration per se (seeKellum, 1998). In patients with mild-to-moderate renal insufficiency, hydration with 0.45% sodium chloride is as good as or better than either mannitol or furosemide in protection against decreases in GFR induced by radiocontrast agents (Soloman et al., 1994). Studies of prophylactic mannitol indicate effectiveness in jaundiced patients undergoing surgery (Dawson, 1965). However, in vascular and open heart surgery, prophylactic mannitol maintains urine flow but not GFR. In established ATN, mannitol will increase urine volume in some patients, and those patients converted from oliguric to nonoliguric ATN appear to recover more rapidly and require less dialysis compared with patients who do not respond to mannitol (Levinsky and Bernard, 1988). However, it is not clear whether these benefits are due to the diuretic or whether "responders" have lesser degrees of renal damage from the outset compared with "nonresponders." Repeated administration of mannitol to nonresponders is not recommended, and nowadays loop diuretics are more frequently used to convert oliguric to nonoliguric ATN. Another use for mannitol and urea is in the treatment of dialysis disequilibrium syndrome. Too rapid a removal of solutes from the extracellular fluid by hemodialysis or peritoneal dialysis results in a reduction in the osmolality of the extracellular fluid. Consequently, water moves from the extracellular compartment into the intracellular compartment, causing hypotension and CNS symptoms (headache, nausea, muscle cramps, restlessness, CNS depression, and convulsions). Osmotic diuretics increase the osmolality of the extracellular fluid compartment and thereby shift water back into the extracellular compartment. By increasing the osmotic pressure of the plasma, osmotic diuretics extract water from the eye and brain. All four osmotic diuretics are used to control intraocular pressure during acute attacks of
  17. glaucoma and for short-term reductions in intraocular pressure, both preoperatively and postoperatively, in patients who require ocular surgery. Also, mannitol and urea are used to reduce cerebral edema and brain mass before and after neurosurgery. Inhibitors of Na +–K+–2 Cl– Symport (Loop Diuretics; High-Ceiling Diuretics) Inhibitors of Na+–K+–2Cl– symport are a group of diuretics that have in common an ability to block the Na+–K+–2Cl– symporter in the thick ascending limb of the loop of Henle; hence these diuretics also are referred to as loop diuretics. Although the proximal tubule reabsorbs approximately 65% of the filtered Na+, diuretics acting only in the proximal tubule have limited efficacy because the thick ascending limb has a great reabsorptive capacity and reabsorbs most of the rejectate from the proximal tubule. Diuretics acting predominantly at sites past the thick ascending limb also have limited efficacy, because only a small percentage of the filtered Na+ load reaches these more distal sites. In contrast, inhibitors of Na+–K+–2Cl– symport are highly efficacious, and for this reason they often are called high-ceiling diuretics. The efficacy of inhibitors of Na+–K+–2Cl– symport in the thick ascending limb of the loop of Henle is due to a combination of two factors: (1) Approximately 25% of the filtered Na+ load normally is reabsorbed by the thick ascending limb; and (2) nephron segments past the thick ascending limb do not possess the reabsorptive capacity to rescue the flood of rejectate exiting the thick ascending limb. Chemistry Inhibitors of Na+–K+–2Cl– symport are a chemically diverse group of drugs (seeTable 29–4). Furosemide, bumetanide, azosemide, piretanide, and tripamide all contain a sulfonamide moiety, whereas ethacrynic acid is a phenoxyacetic acid derivative. Muzolimine has neither of these structural features, and torsemide is a sulfonylurea. Only furosemide ( LASIX ), bumetanide ( BUMEX ), ethacrynic acid (EDECRIN), and torsemide ( DEMADEX ) are available currently in the United States. Mechanism and Site of Action Inhibitors of Na+–K+–2Cl– symport act primarily in the thick ascending limb. Micropuncture of the DCT demonstrates that loop diuretics increase the delivery of solutes out of the loop of Henle (Dirks and Seely, 1970). Also, in situ microperfusion of the loop of Henle (Morgan et al., 1970) and in vitro microperfusion of the CTAL (Burg et al., 1973) indicate inhibition of transport by low concentrations of furosemide in the perfusate. Some inhibitors of Na+–K+–2Cl– symport may have additional effects in the proximal tubule; however, the significance of these effects is unclear. It was initially thought that Cl– was transported by a primary active electrogenic transporter in the luminal membrane independent of Na+. Discovery of furosemide-sensitive Na+–K+–2Cl– symport in other tissues caused Greger (1981) to investigate more carefully the Na+ dependence of Cl– transport in the isolated perfused rabbit CTAL. By scrupulously removing Na+ from the luminal perfusate, Greger demonstrated the dependence of Cl– transport on Na+. It is now well accepted that, in the thick ascending limb, flux of Na+, K+, and Cl– from the lumen into the epithelial cell is mediated by a Na+–K+–2Cl– symporter (seeFigure 29–6). This symporter captures the free energy in the Na+ electrochemical gradient established by the basolateral Na+ pump and provides for "uphill" transport of K+ and Cl– into the cell. K+ channels in the luminal membrane (called ROMK) provide a conductive pathway for the apical recycling of this cation (Ho et al., 1993; Kohda et al., 1998), and basolateral Cl– channels (called CLCN) provide a basolateral exit mechanism for Cl–. The luminal membranes of epithelial cells in the thick ascending limb have conductive pathways
  18. (channels) only for K+; therefore the apical membrane voltage is determined by the equilibrium potential for K+ (EK). In contrast, the basolateral membrane has channels for both K+ and Cl–, so that the basolateral membrane voltage is less than EK; i.e., conductance for Cl– depolarizes the basolateral membrane. Depolarization of the basolateral membrane results in a transepithelial potential difference of approximately 10 mV, with the lumen positive with respect to the interstitial space. This lumen-positive potential difference repels cations (Na +, Ca2+, and Mg2+) and thereby provides an important driving force for the paracellular flux of these cations into the interstitial space. Figure 29–6. NaCl Reabsorption in Thick Ascending Limb and Mechanism of Diuretic Action of Na+–K+–2Cl– Symport Inhibitors. S, symporter; CH, ion channel. Numbers in parentheses indicate stoichiometry. Designated voltages are the potential differences across the indicated membrane or cell. As the name implies, inhibitors of Na+–K+–2Cl– symport bind to the Na+–K+–2Cl– symporter in the thick ascending limb (Koenig et al., 1983) and block its function, bringing salt transport in this segment of the nephron to a virtual standstill (Burg et al., 1973). The molecular mechanism by which this class of drugs blocks the Na+–K+–2Cl– symporter is unknown, but evidence suggests that these drugs attach to the Cl––binding site (Hannafin et al., 1983) located in the symporter's transmembrane domain (Isenring and Forbush, 1997). Inhibitors of Na+–K+–2Cl– symport also inhibit Ca2+ and Mg2+ reabsorption in the thick ascending limb by abolishing the transepithelial potential difference that is the dominant driving force for reabsorption of these cations. Na+–K+–2Cl– symporters are an important family of transport molecules found in many secretory and absorbing epithelia. The rectal gland of the dogfish shark is a particularly rich source of the protein, and a cDNA encoding a Na+–K+–2Cl– symporter was isolated from a cDNA library obtained from the dogfish shark rectal gland by screening with antibodies to the shark symporter (Xu et al., 1994). Molecular cloning revealed a deduced amino acid sequence of 1191 residues
  19. containing 12 putative membrane-spanning domains flanked by long N and C termini in the cytoplasm. Expression of this protein resulted in Na+–K+–2Cl– symport that was sensitive to bumetanide. The shark rectal gland Na+–K+–2Cl– symporter cDNA subsequently was used to screen a human colonic cDNA library, and this provided Na+–K+–2Cl– symporter cDNA probes from this tissue. These latter probes were used to screen rabbit renal cortical and renal medullary libraries, which allowed cloning of the rabbit renal Na+–K+–2Cl– symporter (Payne and Forbush, 1994). This symporter is 1099 amino acids in length, is 61% identical to the dogfish shark secretory Na+–K+– 2Cl– symporter, has 12 predicted transmembrane helices, and contains large N- and C-terminal cytoplasmic regions. Subsequent studies demonstrated that Na+–K+–2Cl– symporters are of two varieties (seeKaplan et al., 1996). The "absorptive" symporter (called ENCC2, NKCC2, or BSC1) is expressed only in the kidney, is localized to the apical membrane of the thick ascending limb, and is regulated by cyclic AMP (Obermüller et al., 1996; Kaplan et al., 1996; Nielsen et al., 1998; Plata et al., 1999). At least six different isoforms of the absorptive symporter are generated by alternative mRNA splicing (Mount et al., 1999). The "secretory" symporter (called ENCC3, NKCC1, or BSC2) is a "housekeeping" protein that is widely expressed and, in epithelial cells, is localized to the basolateral membrane. A model of Na+–K+–2Cl– symport has been proposed based on ordered binding of ions to the symporter (Lytle et al., 1998). Mutations in the genes coding for the absorptive Na+–K+–2Cl– symporter, the apical K+ channel, or the basolateral Cl– channel give rise to Bartter's syndrome (inherited hypokalemic alkalosis with salt wasting and hypotension) (seeSimon and Lifton, 1998). Effects on Urinary Excretion Due to blockade of the Na+–K+–2Cl– symporter, loop diuretics cause a profound increase in the urinary excretion of Na+ and Cl– (i.e., up to 25% of the filtered load of Na+). Abolition of the transepithelial potential difference also results in marked increases in the excretion of Ca 2+ and Mg2+. Some (e.g., furosemide), but not all (e.g., bumetanide and piretanide), sulfonamide-based loop diuretics have weak carbonic anhydrase–inhibiting activity. Those drugs with carbonic anhydrase–inhibiting activity increase the urinary excretion of HCO3– and phosphate. The mechanism by which inhibition of carbonic anhydrase increases phosphate excretion is not known. All inhibitors of Na+–K+–2Cl– symport increase the urinary excretion of K+ and titratable acid. This effect is due in part to increased delivery of Na+ to the distal tubule. The mechanism by which increased distal delivery of Na+ enhances excretion of K+ and H+ is discussed in the section on inhibitors of Na+ channels. Acutely, loop diuretics increase the excretion of uric acid, whereas chronic administration of these drugs results in reduced excretion of uric acid. The chronic effects of loop diuretics on uric acid excretion may be due to enhanced transport in the proximal tubule secondary to volume depletion, leading to increased uric acid reabsorption, or to competition between the diuretic and uric acid for the organic acid secretory mechanism in the proximal tubule, leading to reduced uric acid secretion. By blocking active NaCl reabsorption in the thick ascending limb, inhibitors of Na+–K+–2Cl– symport interfere with a critical step in the mechanism that produces a hypertonic medullary interstitium. Therefore, loop diuretics block the kidney's ability to concentrate urine during hydropenia. Also, since the thick ascending limb is part of the diluting segment, inhibitors of Na+– K+–2Cl– symport markedly impair the kidney's ability to excrete a dilute urine during water diuresis. Effects on Renal Hemodynamics If volume depletion is prevented by replacing fluid losses, inhibitors of Na+–K+–2Cl– symport generally increase total RBF and redistribute RBF to the midcortex (Stein et al., 1972). However,
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