Goodman and Gilman Manual of Pharmacology and Therapeutics
Modulation of Cardiovascular Function
Regulation of Renal Function and Vascular Volume
RENAL ANATOMY AND PHYSIOLOGY
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 ~1 million nephrons. Figure 25–1 illustrates subdivisions of the nephron.
Figure 25–1 Anatomy and nomenclature of the nephron.
GLOMERULAR FILTRATION. In the glomerular capillaries, a portion of plasma water is forced through a filter that has 3 basic components: the fenestrated capillary endothelial cells, a basement membrane lying just beneath the endothelial cells, and the filtration slit diaphragms formed by 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.
OVERVIEW OF NEPHRON FUNCTION. The kidney filters large quantities of plasma, reabsorbs substances that the body must conserve, and leaves behind or secretes substances that must be eliminated. The changing architecture and cellular differentiation along the length of a nephron is crucial to these functions (see Figure 25–1). The 2 kidneys in humans produce together ~120 mL of ultrafiltrate per minute, yet only 1 mL/min of urine is produced. Therefore, >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 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. Normally, ~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 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 (TAL, with 3 segments noted in Figure 25–1). Together the proximal straight tubule, DTL, ATL, and TAL segments 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 TAL 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 TAL, which has a large reabsorptive capacity. The TAL passes between the afferent and efferent arterioles and makes contact with the afferent arteriole by means of 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 or ATP) to the afferent arteriole of the same nephron, causing it to constrict, thereby reducing the glomerular filtration rate (GFR). This homeostatic mechanism, known as tubuloglomerular feedback (TGF), protects the organism from salt and volume wasting. 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). Like the TAL, the DCT actively transports NaCl and is impermeable to water. Because these characteristics impart the ability to produce a dilute urine, the TAL 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 TAL, the DCT does not contribute to the countercurrent-induced hypertonicity of the medullary interstitium (described below).
The collecting duct system (segments 10–14 in Figure 25–1) 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, vasopressin (also called antidiuretic hormone [ADH]) modulates water permeability of this part of the nephron. 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. In the presence of ADH, the collecting duct system is permeable to water, so water is reabsorbed. The movement of water out of the tubule is driven by the steep concentration gradient that exists between tubular fluid and medullary interstitium.
The hypertonicity of the medullary interstitium plays a vital role in the ability of mammals and birds to concentrate urine, which is accomplished by a combination of the unique topography of the loop of Henle and the specialized permeability features of the loop’s subsegments. The “passive countercurrent multiplier hypothesis” proposes that active transport in the TAL concentrates NaCl in the interstitium of the outer medulla. Because 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 urea diffuses into the inner medulla, where it is trapped by countercurrent exchange in the vasa recta. Because 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. There are multiple mechanisms by which solutes may cross cell membranes (see Figure 5–4). The kinds of transport achieved in a nephron segment depend mainly on which transporters are present and whether they are embedded in the luminal or basolateral membrane. Figure 25–2presents a general model of renal tubular transport that be summarized as follows:
Figure 25–2 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.
1. Na+, K+-ATPase (sodium pump) in the basolateral membrane transports Na+ into the intercellular and interstitial spaces and K+ into the cell, establishing an electrochemical gradient for Na+ across the cell membrane directed inward.
2. Na+ can diffuse down this Na+ gradient across the luminal membrane via Na+ channels and via membrane symporters that use the energy stored in the Na+ gradient to transport solutes out of the tubular lumen and into the cell (e.g., Na+-glucose, , and Na+-amino acid) and antiporters (e.g., Na+-H+) that move solutes into the lumen as Na+ moves out of the tubular lumen and into the cell.
3. Na+ exits the basolateral membrane into intercellular and interstitial spaces via the Na+ pump.
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 substrate/solute gradients then permit simple diffusion or mediated transport (e.g., 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 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 by both the trans-cellular (e.g., 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, hydrostatic pressure increases, thus providing a driving force for bulk water flow. Bulk water flow carries solute out of the intercellular space into the interstitial space and, finally, into the peritubular capillaries.
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 or may be actively secreted directly into 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 25–3. Both systems are powered by the sodium pump in the basolateral membrane, involve secondary and tertiary active transport, and use a facilitated-diffusion step. There are at least 9 different organic acid and 5 different organic base transporters (see Chapter 5). A family of organic anion transporters (OATs) links countertransport of organic anions with dicarboxylates (Figure 25–3A).
Figure 25–3 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]; αKG2-, α-ketoglutarate but also other dicarboxylates. BL and LM indicate basolateral and luminal membranes, respectively.
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 TAL, Cl– movement can occur paracellularly. Cl– crosses the luminal membrane by antiport with formate and oxalate (proximal tubule), symport with Na+/K+ (TAL), symport with Na+ (DCT), and antiport with (collecting-duct system). Cl– crosses the basolateral membrane by symport with K+ (proximal tubule and TAL), antiport with Na+/ (proximal tubule), and Cl– channels (TAL, DCT, collecting-duct system).
Eighty to ninety percent of filtered K+ is reabsorbed in the proximal tubule (diffusion and solvent drag) and TAL (diffusion), largely through the paracellular pathway. The DCT and collecting-duct system secrete variable amounts of K+ by a channel-mediated pathway. Modulation of the rate of K+ secretion in the collecting-duct system, particularly by aldosterone, allows urinary K+ excretion to be matched with dietary intake. The transepithelial potential difference (VT), lumen-positive in the TAL and lumen-negative in the collecting-duct system, drives K+ reabsorption and secretion, respectively.
Most of the filtered Ca2+ (~70%) is reabsorbed by the proximal tubule by passive diffusion through a paracellular route. Another 25% of filtered Ca2+ is reabsorbed by the TAL in part by a paracellular route driven by the lumen-positive VT and in part by active transcellular Ca2+ reabsorption modulated by parathyroid hormone (PTH; see Chapter 44). Most of the remaining Ca2+ is reabsorbed in DCT by a transcellular pathway. The transcellular pathway in the TAL and DCT involves passive Ca2+ influx across the luminal membrane through Ca2+ channels (TRPV5), followed by Ca2+ extrusion across the basolateral membrane by a Ca2+-ATPase. Also, in DCT and CNT, Ca2+ crosses the basolateral membrane by Na+-Ca2+ exchanger (antiport). Inorganic phosphate (Pi) is largely reabsorbed (80% of filtered load) by the proximal tubule. The Na+-Pi symporter uses the free energy of the Na+ electrochemical gradient to transport Pi into the cell. The Na+-Pi symporter is inhibited by PTH.
The renal tubules reabsorb and secrete protons (tubular acidification), thereby participating in acid–base balance. These processes are described in the section on carbonic anhydrase inhibitors.
PRINCIPLES OF DIURETIC ACTION
Diuretics are drugs that increase the rate of urine flow; clinically useful diuretics also increase the rate of Na+ excretion (natriuresis) and of an accompanying anion, usually Cl–. Most clinical applications of diuretics are directed toward reducing extracellular fluid volume by decreasing total-body NaCl content.
Although continued diuretic administration causes a sustained net deficit in total-body Na+, the time course of natriuresis is finite because renal compensatory mechanisms bring Na+ excretion in line with Na+ intake, a phenomenon known as diuretic braking. These compensatory mechanisms include activation of the sympathetic nervous system, activation of the renin–angiotensin–aldosterone axis, decreased arterial blood pressure (which reduces pressure natriuresis), renal epithelial cell hypertrophy, increased renal epithelial transporter expression, and perhaps alterations in natriuretic hormones such as atrial natriuretic peptide. The net effects on extracellular volume and body weight are shown in Figure 25–4.
Figure 25–4 Changes in extracellular fluid volume and weight with diuretic therapy. The period of diuretic administration is shown in the shaded box along with its effects on body weight in the upper part of the figure and Na+ excretion in the lower half of the figure. Initially, when Na+ excretion exceeds intake, body weight and extracellular fluid volume (ECFV) decrease. Subsequently, a new steady state is achieved where Na+ intake and excretion are equal but at a lower ECFV and body weight. This results from activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS), “the braking phenomenon.” When the diuretic is discontinued, body weight and ECFV rise during a period where Na+ intake exceeds excretion. A new steady state is then reached as stimulation of the RAAS and SNS wane.
Diuretics may modify renal handling of other cations (e.g., K+, H+, Ca2+, and Mg2+), anions (e.g., Cl–, , and ), and uric acid. In addition, diuretics may alter renal hemodynamics indirectly. Table 25–1 gives a comparison of the general effects of the major diuretic classes.
Excretory and Renal Hemodynamic Effects of Diureticsa
INHIBITORS OF CARBONIC ANHYDRASE
There are 3 orally administered carbonic anhydrase inhibitors—acetazolamide, dichlorphenamide (not marketed in the U.S.), and methazolamide (Table 25–2).
Inhibitors of Carbonic Anhydrase
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), as well as in the cytoplasm (type II carbonic anhydrase) (Figure 25–5). Carbonic anhydrase plays a role in NaHCO3 reabsorption and acid secretion.
Figure 25–5 Sites and mechanisms of action of diuretics. Three important features are noteworthy:
In the proximal tubule, the free energy in the Na+ gradient established by the basolateral Na+ pump is used by a Na+-H+ antiporter (a.k.a. Na+-H+ exchanger [NHE]) in the luminal membrane to transport H+into the tubular lumen in exchange for Na+. In the lumen, H+ reacts with filtered to form H2CO3, which decomposes rapidly to CO2 and water in the presence of carbonic anhydrase in the brush border. Carbonic anhydrase reversibly accelerates this reaction several thousand fold. CO2 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. Continued operation of the Na+-H+ antiporter maintains a low proton concentration in the cell, so H2CO3 ionizes spontaneously to form H+ and , creating an electrochemical gradient for across the basolateral membrane. The electrochemical gradient for is used by a Na+- symporter (a.k.a. the Na+- co-transporter [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 by the paracellular pathway.
Carbonic anhydrase inhibitors potently inhibit both the membrane-bound and cytoplasmic forms of carbonic anhydrase, resulting in nearly complete abolition of NaHCO3 reabsorption in the proximal tubule. Because of the large excess of carbonic anhydrase in proximal tubules, a high percentage 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, which 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 excretion to ~35% of filtered load. This, along with inhibition of titratable acid and NH4+ secretion in the collecting-duct system, results in an increase in urinary pH to ~8 and development of a metabolic acidosis. However, even with a high degree of inhibition of carbonic anhydrase, 65% of is rescued from excretion. The loop of Henle 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, 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 in part secondary to increased delivery of Na+ to the distal nephron, as described in the section on inhibitors of Na+ channels. The effects of carbonic anhydrase inhibitors on renal excretion are self-limiting, probably because the resulting metabolic acidosis decreases the filtered load of to the point that the uncatalyzed reaction between CO2 and water is sufficient to achieve reabsorption.
EFFECTS ON RENAL HEMODYNAMICS. By inhibiting proximal reabsorption, carbonic anhydrase inhibitors increase delivery of solutes to the macula densa. This triggers TGF, which increases afferent arteriolar resistance and reduces renal blood flow (RBF) and GFR.
OTHER ACTIONS. These agents have extrarenal sites of action. Carbonic anhydrase in the ciliary processes of the eye mediates formation of in aqueous humor. 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 due in part to the production of metabolic acidosis; however, direct actions of acetazolamide in the CNS also contribute to its anticonvulsant action. Owing to interference with carbonic anhydrase activity in erythrocytes, carbonic anhydrase inhibitors increase CO2 levels in peripheral tissues and decrease CO2 levels in expired gas. Acetazolamide causes vasodilation by opening vascular Ca2+-activated K+ channels; however, the clinical significance of this effect is unclear.
ABSORPTION AND ELIMINATION. See Table 25–2 for pharmacokinetic data.
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, sulfonamide-like renal lesions, and allergic reactions. 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 or worsen hepatic encephalopathy (the drugs are contraindicated in patients with hepatic cirrhosis); (2) calculus formation and ureteral colic owing 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) reduction of the urinary excretion rate of weak organic bases.
THERAPEUTIC USES. The efficacy of carbonic anhydrase inhibitors as single agents is low. 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+ (<0.2%) who are resistant to diuretic monotherapy. Even so, the long-term usefulness of carbonic anhydrase inhibitors often is compromised by the development of metabolic acidosis. The major indication for carbonic anhydrase inhibitors is open-angle glaucoma. Two products developed specifically for this use are dorzolamide (TRUSOPT, others) and brinzolamide (AZOPT), which are available only as ophthalmic drops. Carbonic anhydrase inhibitors also may be employed for secondary glaucoma and preoperatively in acute angle-closure glaucoma to lower intraocular pressure before surgery (see Chapter 64). Acetazolamide also is used for the treatment of epilepsy (see Chapter 21). Acetazolamide can provide symptomatic relief in patients with high-altitude illness or mountain sickness. Acetazolamide also is useful in patients with familial periodic paralysis. The mechanism for the beneficial effects of acetazolamide in altitude sickness and familial periodic paralysis may be related to the induction of a metabolic acidosis. Finally, carbonic anhydrase inhibitors can be useful for correcting a metabolic alkalosis, especially one caused by diuretic-induced increases in H+ excretion.
Osmotic diuretics are freely filtered at the glomerulus, undergo limited reabsorption by the renal tubule, and are relatively inert pharmacologically. Osmotic diuretics are administered in doses large enough to increase significantly the osmolality of plasma and tubular fluid. Table 25–3 lists 4 osmotic diuretics—glycerin (OSMOGLYN), isosorbide, mannitol (OSMITROL, others), and urea (currently not available in the U.S.).
MECHANISM AND SITE OF ACTION. Osmotic diuretics act both in proximal tubule and loop of Henle, with the latter being the primary site of action. By extracting water from intracellular compartments, osmotic diuretics expand 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. 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 osmotic diuretics inhibit Mg2+ reabsorption in the TAL.
EFFECTS ON URINARY EXCRETION. Osmotic diuretics increase urinary excretion of nearly all electrolytes, including Na+, K+, Ca2+, Mg2+, Cl–, , and phosphate.
EFFECTS ON RENAL HEMODYNAMICS. Osmotic diuretics increase RBF by a variety of mechanisms, but total GFR is little changed.
ABSORPTION AND ELIMINATION. Pharmacokinetic data on the osmotic diuretics are gathered in Table 25–3. Glycerin and isosorbide can be given orally, whereas mannitol and urea must be administered intravenously.
TOXICITY, ADVERSE EFFECTS, CONTRAINDICATIONS, AND 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 the common adverse effects, including headache, nausea, and vomiting. Conversely, loss of water in excess of electrolytes can cause hypernatremia and dehydration. Osmotic diuretics are contraindicated in patients who are anuric owing to severe renal disease. 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. One use for mannitol is in the treatment of dialysis disequilibrium syndrome. Overly removing solutes from the extracellular fluid by hemodialysis results in a reduction in the osmolality of 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 plasma, osmotic diuretics extract water from the eye and brain. All osmotic diuretics are used to control intraocular pressure during acute attacks of 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+-2CL- SYMPORT (LOOP DIURETICS, HIGH-CEILING DIURETICS)
These diuretics inhibit activity of the Na+-K+-2Cl– symporter in the TAL of the loop of Henle, hence the moniker loop diuretics. Although the proximal tubule reabsorbs ~65% of filtered Na+, diuretics acting only in the proximal tubule have limited efficacy because the TAL has the capacity to reabsorb most of the rejectate from the proximal tubule. In contrast, inhibitors of Na+-K+-2Cl– symport in the TAL, sometimes called high-ceiling diuretics, are highly efficacious because (1) ~25% of the filtered Na+ load normally is reabsorbed by the TAL, and (2) nephron segments past the TAL do not possess the resorptive capacity to rescue the flood of rejectate exiting the TAL.
Of the inhibitors of Na+-K+-2Cl– symport (Table 25–4), only furosemide (LASIX), bumetanide (BUMEX), ethacrynic acid (EDECRIN), and torsemide (DEMADEX) are available currently in the U.S. Furosemide and bumetanide contain a sulfonamide moiety. Ethacrynic acid is a phenoxyacetic acid derivative; torsemide is a sulfonylurea. All loop diuretics except torsemide are available as oral and injectable formulations.
Inhibitors of Na+–K+–2Cl- Symport (Loop Diuretics, High-Ceiling Diuretics)
MECHANISM AND SITE OF ACTION. These agents act primarily in the TAL, where the flux of Na+, K+, and Cl– from the lumen into epithelial cells is mediated by a Na+-K+-2Cl– symporter (Figure 25–5). Inhibitors of Na+-K+-2Cl– symport block its function, bringing salt transport in this segment of the nephron to a virtual standstill. Evidence suggests that these drugs attach to the Cl– binding site located in the symporter’s transmembrane domain. Inhibitors of Na+K+-2Cl– symport also inhibit Ca2+ and Mg2+ reabsorption in the TAL by abolishing the transepithelial potential difference that is the dominant driving force for reabsorption of these cations. Na+-K+-2Cl– symporters are found in many secretory and absorbing epithelia. The Na+-K+-2Cl– symporters are of 2 varieties. The “absorptive” symporter (called ENCC2, NKCC2, or BSCl) is expressed only in the kidney, is localized to the apical membrane and subapical intracellular vesicles of the TAL, and is regulated by cyclic AMP/PKA. The “secretory” symporter (called ENCC3, NKCCl, or BSC2) is a “housekeeping” protein that is expressed widely and, in epithelial cells, is localized to the basolateral membrane. The affinity of loop diuretics for the secretory symporter is somewhat less than for the absorptive symporter (e.g., 4-fold difference for bumetanide).
EFFECTS ON URINARY EXCRETION. Loop diuretics increase urinary Na+ and Cl– excretion profoundly (i.e., up to 25% of the filtered Na+ load) and markedly increase Ca2+ and Mg2+ excretion. Furosemide has weak carbonic anhydrase–inhibiting activity and thus increases urinary excretion of and phosphate. All inhibitors of Na+-K+-2Cl– symport increase urinary K+ and titratable acid excretion. This effect is due in part to increased Na+ delivery to the distal tubule (the mechanism by which increased distal Na+ delivery enhances K+ and H+ excretion is discussed in the section on Na+channel inhibitors). Other mechanisms contributing to enhanced K+ and H+ excretion include flow-dependent enhancement of ion secretion by the collecting duct, nonosmotic vasopressin release, and activation of the renin–angiotensin–aldosterone axis.
Acutely, loop diuretics increase uric acid excretion; their chronic administration results in reduced uric acid excretion. Chronic effects of loop diuretics on uric acid excretion may be due to enhanced proximal tubule transport or secondary to volume depletion or to competition between diuretic and uric acid for the organic acid secretory mechanism in proximal tubule. Asymptomatic hyperuricemia is a common consequence of loop diuretics, but painful episodes of gout are rarely reported. By blocking active NaCl reabsorption in the TAL, 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. Also, because the TAL 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. The mechanism of the increase in RBF is not known, but may involve prostaglandins: nonsteroidal anti-inflammatory drugs (NSAIDs) attenuate the diuretic response to loop diuretics in part by preventing prostaglandin-mediated increases in RBF. Loop diuretics block TGF by inhibiting salt transport into the macula densa so that the macula densa no longer can detect NaCl concentrations in the tubular fluid. Therefore, unlike carbonic anhydrase inhibitors, loop diuretics do not decrease GFR by activating TGF. Loop diuretics are powerful stimulators of renin release. This effect is due to interference with NaCl transport by the macula densa and, if volume depletion occurs, to reflex activation of the sympathetic nervous system and stimulation of the intrarenal baroreceptor mechanism.
OTHER ACTIONS. Loop diuretics, particularly furosemide, acutely increase systemic venous capacitance and thereby decrease left ventricular filling pressure. This effect, which may be mediated by prostaglandins and requires intact kidneys, benefits patients with pulmonary edema even before diuresis ensues. High doses of inhibitors of Na+-K+-2Cl– symport can inhibit electrolyte transport in many tissues, but this effect is clinically important only in the inner ear.
ABSORPTION AND ELIMINATION. Table 25–4 presents some pharmacokinetic properties of the agents. Because these drugs are bound extensively to plasma proteins, delivery of these drugs to the tubules by filtration is limited. However, they are secreted efficiently by the organic acid transport system in the proximal tubule, and thereby gain access to the Na+-K+-2Cl– symporter in the luminal membrane of the TAL. Approximately 65% of furosemide is excreted unchanged in urine, and the remainder is conjugated to glucuronic acid in the kidney. Thus, in patients with renal disease, the elimination t1/2 of furosemide is prolonged. Bumetanide and torsemide have significant hepatic metabolism, so liver disease can prolong the elimination t1/2 of these loop diuretics. Oral bioavailability of furosemide varies (10-100%). In contrast, oral availabilities of bumetanide and torsemide are reliably high. Heart failure patients have fewer hospitalizations and better quality of life with torsemide than with furosemide, perhaps because of its more reliable absorption.
As a class, loop diuretics have short elimination half lives; prolonged-release preparations are not available. Consequently, often the dosing interval is too short to maintain adequate levels of loop diuretics in the tubular lumen. Note that torsemide has a longer t1/2 than other agents available in the U.S. As the concentration of loop diuretic in the tubular lumen declines, nephrons begin to avidly reabsorb Na+, which often nullifies the overall effect of the loop diuretic on total-body Na+. This phenomenon of “postdiuretic Na+ retention” can be overcome by restricting dietary Na+ intake or by more frequent administration of the loop diuretic.
TOXICITY, ADVERSE EFFECTS, CONTRAINDICATIONS, DRUG INTERACTIONS. Most adverse effects are due to abnormalities of fluid and electrolyte balance. Overzealous use of loop diuretics can cause serious depletion of total-body Na+. This may manifest as hyponatremia and/or extracellular fluid volume depletion associated with hypotension, reduced GFR, circulatory collapse, thromboembolic episodes, and in patients with liver disease, hepatic encephalopathy. Increased Na+ delivery to the distal tubule, particularly when combined with activation of the renin–angiotensin system, leads to increased urinary K+ and H+ excretion, causing a hypochloremic alkalosis. If dietary K+ intake is not sufficient, hypokalemia may develop, and this may induce cardiac arrhythmias, particularly in patients taking cardiac glycosides. Increased Mg2+ and Ca2+ excretion may result in hypomagnesemia (a risk factor for cardiac arrhythmias) and hypocalcemia (rarely leading to tetany). Loop diuretics should be avoided in postmenopausal osteopenic women, in whom increased Ca2+ excretion may have deleterious effects on bone metabolism.
Loop diuretics can cause ototoxicity that manifests as tinnitus, hearing impairment, deafness, vertigo, and a sense of fullness in the ears. Hearing impairment and deafness are usually, but not always, reversible. Ototoxicity occurs most frequently with rapid intravenous administration and least frequently with oral administration. Ethacrynic acid appears to induce ototoxicity more often than do other loop diuretics and should be reserved for use only in patients who cannot tolerate other loop diuretics. Loop diuretics also can cause hyperuricemia (occasionally leading to gout) and hyperglycemia (infrequently precipitating diabetes mellitus) and can increase plasma levels of LDL cholesterol and triglycerides while decreasing plasma levels of HDL cholesterol. Other adverse effects include skin rashes, photosensitivity, paresthesias, bone marrow depression, and GI disturbances. Contraindications to the use of loop diuretics include severe Na+ and volume depletion, hypersensitivity to sulfonamides (for sulfonamide-based loop diuretics), and anuria unresponsive to a trial dose of loop diuretic.
Drug interactions may occur when loop diuretics are coadministered with:
• Aminoglycosides, carboplatin, paclitaxel, and others (synergism of ototoxicity)
• Anticoagulants (increased anticoagulant activity)
• Digitalis glycosides (increased digitalis-induced arrhythmias)
• Lithium (increased plasma levels of lithium)
• Propranolol (increased plasma levels of propranolol)
• Sulfonylureas (hyperglycemia)
• Cisplatin (increased risk of diuretic-induced ototoxicity)
• NSAIDs (blunted diuretic response and salicylate toxicity with high doses of salicylates)
• Probenecid (blunted diuretic response)
• Thiazide diuretics (synergism of diuretic activity of both drugs leading to profound diuresis)
• Amphotericin B (increased potential for nephrotoxicity and intensification of electrolyte imbalance)
THERAPEUTIC USES. A major use of loop diuretics is in the treatment of acute pulmonary edema. A rapid increase in venous capacitance in conjunction with a brisk natriuresis reduces left ventricular filling pressures and thereby rapidly relieves pulmonary edema. Loop diuretics also are used widely for treatment of chronic congestive heart failure when diminution of extracellular fluid volume is desirable to minimize venous and pulmonary congestion (see Chapter 28). Diuretics cause a significant reduction in mortality and the risk of worsening heart failure, as well as an improvement in exercise capacity. Diuretics are used widely for treatment of hypertension (see Chapter 28). Na+-K+-2Cl– symport inhibitors appear to lower blood pressure as effectively as Na+-Cl– symport inhibitors while causing smaller perturbations in the lipid profile. However, the relative potency and short elimination half-lives of loop diuretics render them less useful for hypertension than thiazide-type diuretics.
The edema of nephrotic syndrome often is refractory to less potent diuretics, and loop diuretics often are the only drugs capable of reducing the massive edema associated with this renal disease. Loop diuretics also are employed in the treatment of edema and ascites of liver cirrhosis; however, care must be taken not to induce volume contraction. In patients with a drug overdose, loop diuretics can be used to induce a forced diuresis to facilitate more rapid renal elimination of the offending drug. Loop diuretics, combined with isotonic saline administration to prevent volume depletion, are used to treat hypercalcemia. Loop diuretics interfere with the kidney’s capacity to produce a concentrated urine. Consequently, loop diuretics combined with hypertonic saline are useful for the treatment of life-threatening hyponatremia. Loop diuretics also are used to treat edema associated with chronic kidney disease, in which the dose-response curve may be right-shifted, requiring higher doses of the loop diuretic (see Figure 25–8 in the 12th edition of the parent text).
Figure 25–8 Interrelationships among renal function, Na+ intake, water homeostasis, distribution of extracellular fluid volume, and mean arterial blood pressure. Pathophysiological mechanisms of edema formation. 1. Rightward shift of renal pressure natriuresis curve. 2. Excessive dietary Na+ intake. 3. Increased distribution of extracellular fluid volume (ECFV) to peritoneal cavity (e.g., liver cirrhosis with increased hepatic sinusoidal hydrostatic pressure) leading to ascites formation. 4. Increased distribution of ECFV to lungs (e.g., left-sided heart failure with increased pulmonary capillary hydrostatic pressure) leading to pulmonary edema. 5. Increased distribution of ECFV to venous circulation (e.g., right-sided heart failure) leading to venous congestion. 6. Peripheral edema caused by altered Starling forces causing increased distribution of ECFV to interstitial space (e.g., diminished plasma proteins in nephrotic syndrome, severe burns, and liver disease).
INHIBITORS OF NA+-CL- SYMPORT (THIAZIDE AND THIAZIDE-LIKE DIURETICS)
The term thiazide diuretics generally refers to all inhibitors of Na+-Cl– symport (Table 25–5), so named because the original inhibitors of Na+-Cl– symport were benzothiadiazine derivatives. The class now includes drugs that are pharmacologically similar to thiazide diuretics but differ structurally (thiazide-like diuretics).
Inhibitors of Na+-Cl- Symport (Thiazide and Thiazide-like Diuretics)
MECHANISM AND SITE OF ACTION. Thiazide diuretics inhibit NaCl transport in DCT; the proximal tubule may represent a secondary site of action.
Figure 25–5 illustrates the current model of electrolyte transport in DCT. Transport is powered by a Na+ pump in the basolateral membrane. Free energy in the electrochemical gradient for Na+ is harnessed by a Na+-Cl– symporter in the luminal membrane that moves Cl– into the epithelial cell against its electrochemical gradient. Cl– then exits the basolateral membrane passively by a Cl– channel. Thiazide diuretics inhibit the Na+-Cl– symporter (called ENCCl or TSC) that is expressed predominantly in kidney and localized to the apical membrane of DCT epithelial cells. Expression of the symporter is regulated by aldosterone. Mutations in the Na+-Cl– symporter cause a form of inherited hypokalemic alkalosis called Gitelman syndrome.
EFFECTS ON URINARY EXCRETION. Inhibitors of Na+-Cl– symport increase Na+ and Cl– excretion. However, thiazides are only moderately efficacious (i.e., maximum excretion of filtered Na+ load is only 5%) because ~90% of the filtered Na+ load is reabsorbed before reaching the DCT. Some thiazide diuretics also are weak inhibitors of carbonic anhydrase, an effect that increases and phosphate excretion and probably accounts for their weak proximal tubular effects. Inhibitors of Na+-Cl– symport increase K+ and titratable acid excretion by the same mechanisms discussed for loop diuresis. Acute thiazide administration increases uric acid excretion. However, uric acid excretion is reduced following chronic administration by the same mechanisms discussed for loop diuretics. Acute effects of inhibitors of Na+-Cl– symport on Ca2+ excretion are variable; when administered chronically, thiazide diuretics decrease Ca2+ excretion. The mechanism involves increased proximal reabsorption owing to volume depletion, as well as direct effects of thiazides to increase Ca2+ reabsorption in the DCT. Thiazide diuretics may cause a mild magnesuria; long-term use of thiazide diuretics may cause magnesium deficiency, particularly in the elderly. Because inhibitors of Na+-Cl– symport inhibit transport in the cortical diluting segment, thiazide diuretics attenuate the kidney’s ability to excrete dilute urine during water diuresis. However, since the DCT is not involved in the mechanism that generates a hypertonic medullary interstitium, thiazide diuretics do not alter the kidney’s ability to concentrate urine during hydropenia. In general, inhibitors of Na+-Cl– symport do not affect RBF and only variably reduce GFR owing to increases in intratubular pressure. Thiazides have little or no influence on TGF.
ABSORPTION AND ELIMINATION. Table 25–5 lists pharmacokinetic parameters of Na+-Cl– symport inhibitors. Note the wide range of half-lives for these drugs. Sulfonamides, as organic acids, are secreted into the proximal tubule by the organic acid secretory pathway. Because thiazides must gain access to the tubular lumen to inhibit the Na+-Cl– symporter, drugs such as probenecid can attenuate the diuretic response to thiazides by competing for transport into proximal tubule. However, plasma protein binding varies considerably among thiazide diuretics, and this parameter determines the contribution that filtration makes to tubular delivery of a specific thiazide.
TOXICITY, ADVERSE EFFECTS, CONTRAINDICATIONS, DRUG INTERACTIONS. Thiazide diuretics rarely cause CNS (e.g., vertigo, headache), GI, hematological, and dermatological (e.g., photosensitivity and skin rashes) disorders. The incidence of erectile dysfunction is greater with Na+-Cl– symport inhibitors than with several other antihypertensive agents, but usually is tolerable. As with loop diuretics, most serious adverse effects of thiazides are related to abnormalities of fluid and electrolyte balance. These adverse effects include extracellular volume depletion, hypotension, hypokalemia, hyponatremia, hypochloremia, metabolic alkalosis, hypomagnesemia, hypercalcemia, and hyperuricemia. Thiazide diuretics have caused fatal or near-fatal hyponatremia, and some patients are at recurrent risk of hyponatremia when rechallenged with thiazides.
Thiazide diuretics also decrease glucose tolerance, and latent diabetes mellitus. The mechanism of impaired glucose tolerance appears to involve reduced insulin secretion and alterations in glucose metabolism. Hyperglycemia is reduced when K+ is given along with the diuretic. Thiazide-induced hypokalemia also impairs the antihypertensive effect and cardiovascular protection afforded by thiazides in patients with hypertension. Thiazide diuretics also may increase plasma levels of LDL cholesterol, total cholesterol, and total triglycerides. Thiazide diuretics are contraindicated in individuals who are hypersensitive to sulfonamides. Thiazide diuretics may diminish the effects of anticoagulants, uricosuric agents used to treat gout, sulfonylureas, and insulin and may increase the effects of anesthetics, diazoxide, digitalis glycosides, lithium, loop diuretics, and vitamin D. The effectiveness of thiazide diuretics may be reduced by NSAIDs, nonselective or selective COX-2 inhibitors, and bile acid sequestrants (reduced absorption of thiazides). Amphotericin B and corticosteroids increase the risk of hypokalemia induced by thiazide diuretics.
A potentially lethal drug interaction warranting special emphasis is that involving thiazide diuretics and quinidine. Prolongation of the QT interval by quinidine can lead to the development of polymorphic ventricular tachycardia (torsade de pointes; see Chapter 29). Torsade de pointes may deteriorate into fatal ventricular fibrillation. Hypokalemia increases the risk of quinidine-induced torsade de pointes, and thiazide diuretic–induced K+ depletion may account for many cases of quinidine-induced torsade de pointes.
THERAPEUTIC USES. Thiazide diuretics are used for the treatment of edema associated with diseases of the heart (congestive heart failure), liver (hepatic cirrhosis), and kidney (nephrotic syndrome, chronic renal failure, and acute glomerulonephritis). With the possible exceptions of metolazone and indapamide, most thiazide diuretics are ineffective when the GFR is <l30-40 mL/min. Thiazide diuretics decrease blood pressure in hypertensive patients and are used widely for the treatment of hypertension either alone or in combination with other antihypertensive drugs (see Chapter 27). Thiazide diuretics are inexpensive, as efficacious as other classes of antihypertensive agents, and well tolerated. Thiazides can be administered once daily, do not require dose titration, and have few contraindications. Moreover, thiazides have additive or synergistic effects when combined with other classes of antihypertensive agents.
Thiazide diuretics, which reduce urinary Ca2+ excretion, sometimes are employed to treat Ca2+ nephrolithiasis and may be useful for treatment of osteoporosis (see Chapter 44). Thiazide diuretics also are the mainstay for treatment of nephrogenic diabetes insipidus, reducing urine volume by up to 50%. Although it may seem counterintuitive to treat a disorder of increased urine volume with a diuretic, thiazides reduce the kidney’s ability to excrete free water: They increase proximal tubular water reabsorption (secondary to volume contraction) and block the ability of the DCT to form dilute urine. This latter effect results in an increase in urine osmolality. Because other halides are excreted by renal processes similar to those for Cl–, thiazide diuretics may be useful for the management of Br- intoxication.
INHIBITORS OF RENAL EPITHELIAL NA+ CHANNELS (K+-SPARING DIURETICS)
Triamterene (DYRENIUM) and amiloride (MIDAMOR) are the only 2 drugs of this class in clinical use. Both drugs cause small increases in NaCl excretion and usually are employed for their anti-kaliuretic actions to offset the effects of other diuretics that increase K+ excretion. Consequently, triamterene and amiloride, along with spironolactone (described in the next section), often are classified as potassium (K+)-sparing diuretics.
Both drugs are organic bases and are transported by the organic base secretory mechanism in proximal tubule and have similar mechanisms of action (Figure 25–5). Principal cells in the late distal tubule and collecting duct have, in their luminal membranes, epithelial Na+ channels that provide a conductive pathway for Na+ entry into the cell down the electrochemical gradient created by the basolateral Na+pump. The higher permeability of the luminal membrane for Na+ depolarizes the luminal membrane but not the basolateral membrane, creating a lumen-negative transepithelial potential difference. This transepithelial voltage provides an important driving force for the secretion of K+ into the lumen by K+ channels (ROMK) in the luminal membrane. Carbonic anhydrase inhibitors, loop diuretics, and thiazide diuretics increase Na+ delivery to the late distal tubule and collecting duct, a situation that often is associated with increased K+ and H+ excretion.
Amiloride blocks epithelial Na+ channels in the luminal membrane of principal cells in late distal tubule and collecting duct. The amiloride-sensitive Na+ channel (called ENaC) consists of 3 subunits (α, β, and γ). Although the α subunit is sufficient for channel activity, maximal Na+ permeability is induced when all 3 subunits are coexpressed in the same cell, probably forming a tetrameric structure consisting of 2 α subunits, 1 β subunit, and 1 γ subunit. Liddle syndrome is an autosomal dominant form of low-renin, volume-expanded hypertension that is due to mutations in the β or γ subunits, leading to increased basal ENaC activity.
EFFECTS ON URINARY EXCRETION. The late distal tubule and collecting duct have a limited capacity to reabsorb solutes, thus, Na+ channel blockade in this part of the nephron increases Na+ and Cl–excretion rates only mildly (~2% of filtered load). Blockade of Na+ channels hyperpolarizes the luminal membrane, reducing the lumen-negative transepithelial voltage. Because the lumen-negative potential difference normally opposes cation reabsorption and facilitates cation secretion, attenuation of the lumen-negative voltage decreases K+, H+, Ca2+, and Mg2+ excretion rates. Volume contraction may increase reabsorption of uric acid in the proximal tubule; hence chronic administration of amiloride and triamterene may decrease uric acid excretion. Amiloride and triamterene have little or no effect on renal hemodynamics and do not alter TGF.
ABSORPTION AND ELIMINATION. Table 25–6 lists pharmacokinetic data for amiloride and triamterene. Amiloride is eliminated predominantly by urinary excretion of intact drug. Triamterene is metabolized in the liver to an active metabolite, 4-hydroxytriamterene sulfate, and this metabolite is excreted in urine. Therefore, triamterene toxicity may be enhanced in both hepatic disease and renal failure.
Inhibitors of Renal Epithelial Na+ Channels (K+-Sparing Diuretics)
TOXICITY, ADVERSE EFFECTS, CONTRAINDICATIONS, DRUG INTERACTIONS. The most dangerous adverse effect of renal Na+-channel inhibitors is hyperkalemia, which can be life threatening. Consequently, amiloride and triamterene are contraindicated in patients with hyperkalemia, as well as in patients at increased risk of developing hyperkalemia (e.g., patients with renal failure, patients receiving other K+-sparing diuretics, patients taking angiotensin-converting enzyme inhibitors, or patients taking K+ supplements). Even NSAIDs can increase the likelihood of hyperkalemia in patients receiving Na+-channel inhibitors. Routine monitoring of the serum K+ level is essential in patients receiving K+-sparing diuretics. Cirrhotic patients are prone to megaloblastosis because of folic acid deficiency, and triamterene, a weak folic acid antagonist, may increase the likelihood of this adverse event. Triamterene also can reduce glucose tolerance and induce photosensitization and has been associated with interstitial nephritis and renal stones. Both drugs can cause CNS, GI, musculoskeletal, dermatological, and hematological adverse effects. The most common adverse effects of amiloride are nausea, vomiting, diarrhea, and headache; those of triamterene are nausea, vomiting, leg cramps, and dizziness.
THERAPEUTIC USES. Because of the mild natriuresis induced by Na+-channel inhibitors, these drugs seldom are used as sole agents in treatment of edema or hypertension; their major utility is in combination with other diuretics. Coadministration of a Na+-channel inhibitor augments the diuretic and antihypertensive response to thiazide and loop diuretics. More important, the ability of Na+-channel inhibitors to reduce K+ excretion tends to offset the kaliuretic effects of thiazide and loop diuretics and to result in normal plasma K+ values.
Liddle syndrome can be treated effectively with Na+-channel inhibitors. Aerosolized amiloride has been shown to improve mucociliary clearance in patients with cystic fibrosis. By inhibiting Na+absorption from the surfaces of airway epithelial cells, amiloride augments hydration of respiratory secretions and thereby improves mucociliary clearance. Amiloride also is useful for lithium-induced nephrogenic diabetes insipidus because it blocks Li+ transport into collecting tubule cells.
ANTAGONISTS OF MINERALOCORTICOID RECEPTORS (ALDOSTERONE ANTAGONISTS, K+-SPARING DIURETICS)
Mineralocorticoids cause salt and water retention and increase K+ and H+ excretion by binding to specific mineralocorticoid receptors (MRs). Two MR antagonists are available in the U.S., spironolactone and eplerenone (Table 25–7).
Mineralocorticoid Receptor Antagonists (Aldosterone Antagonists, K+-Sparing Diuretics)
MECHANISM AND SITE OF ACTION (FIGURE 25–6). Epithelial cells in late distal tubule and collecting duct contain cytosolic MRs with a high aldosterone affinity. When aldosterone binds to MRs, the MR-aldosterone complex translocates to the nucleus, where regulates the expression of multiple gene products called aldosterone-induced proteins (AIPs). Consequently, transepithelial NaCl transport is enhanced, and the lumen-negative transepithelial voltage is increased. The latter effect increases the driving force for K+ and H+ secretion into the tubular lumen.
Figure 25–6 Effects of aldosterone on late distal tubule and collecting duct and diuretic mechanism of aldosterone antagonists. A. Cortisol also has affinity for the mineralocorticoid receptor (MR), but is inactivated in the cell by 11-v-hydroxysteroid dehydrogenase (HSD) type II. B. Serum and glucorticoid-regulated kinase (SGK)-1 is upregulated by aldosterone. SGK-1 phosphorylates and inactivates Nedd4-2, a ubiquitin-protein ligase that acts on ENaC, leading to its degradation. Phosphorylated Nedd4-2 no longer interacts with the PY motif of ENaC; as a result, the protein is not ubiquitinated and remains in the membrane, leading to increased Na+ entry into the cell.
1. Activation of membrane-bound Na+ channels
2. Na+ channel (ENaC) removal from the membrane inhibited
3. De novo synthesis of Na+ channels
4. Activation of membrane-bound Na+,K+-ATPase
5. Redistribution of Na+,K+-ATPase from cytosol to membrane
6. De novo synthesis of Na+,K+-ATPase
7. Changes in permeability of tight junctions
8. Increased mitochondrial production of ATP
AIP, aldosterone-induced proteins; ALDO, aldosterone; CH, ion channel; BL, basolateral membrane; LM, luminal membrane.
Drugs such as spironolactone and eplerenone competitively inhibit the binding of aldosterone to the MR. Unlike the MR-aldosterone complex, the MR-spironolactone complex is not able to induce the synthesis of AIPs. Since spironolactone and eplerenone block biological effects of aldosterone, these agents also are referred to as aldosterone antagonists. MR antagonists are the only diuretics that do not require access to the tubular lumen to induce diuresis.
EFFECTS ON URINARY EXCRETION. The effects of MR antagonists on urinary excretion are very similar to those induced by renal epithelial Na+-channel inhibitors. However, unlike Na+-channel inhibitors, the clinical efficacy of MR antagonists is a function of endogenous aldosterone levels. The higher the endogenous aldosterone level, the greater the effects of MR antagonists on urinary excretion. MR antagonists have little or no effect on renal hemodynamics and do not alter TGF.
OTHER ACTIONS. Spironolactone has some affinity toward progesterone and androgen receptors and thereby induces side effects such as gynecomastia, impotence, and menstrual irregularities. Owing to its 9,11-epoxide group, eplerenone has very low affinity for progesterone and androgen receptors (<1% and <0.1%, respectively) compared with spironolactone. High spironolactone concentrations can interfere with steroid biosynthesis by inhibiting steroid hydroxylases; these effects have limited clinical relevance.
ABSORPTION AND ELIMINATION. Spironolactone is absorbed partially (~65%), is metabolized extensively (even during its first passage through the liver), undergoes enterohepatic recirculation, is highly protein bound, and has a short t1/2 (~1.6 h). The t1/2 is prolonged to 9 h in patients with cirrhosis. Eplerenone has good oral availability and is eliminated primarily by metabolism by CYP3A4 to inactive metabolites, with a t1/2 of ~5 h. Canrenone and K+ canrenoate also are in clinical use. Canrenoate is not active but is converted to canrenone.
TOXICITY, ADVERSE EFFECTS, CONTRAINDICATIONS, DRUG INTERACTIONS. Hyperkalemia is the principal risk of MR antagonists. Therefore, these drugs are contraindicated in patients with hyperkalemia and in those at increased risk of developing hyperkalemia. MR antagonists also can induce metabolic acidosis in cirrhotic patients. Salicylates may reduce the tubular secretion of canrenone and decrease diuretic efficacy of spironolactone. Spironolactone may alter the clearance of cardiac glycosides. Owing to its affinity for other steroid receptors, spironolactone may cause gynecomastia, impotence, decreased libido, hirsutism, deepening of the voice, and menstrual irregularities. Spironolactone also may induce diarrhea, gastritis, gastric bleeding, and peptic ulcers (the drug is contraindicated in patients with peptic ulcers). CNS adverse effects include drowsiness, lethargy, ataxia, confusion, and headache. Spironolactone may cause skin rashes and, rarely, blood dyscrasias. Strong inhibitors of CYP3A4 may increase plasma levels of eplerenone, and such drugs should not be administered to patients taking eplerenone, and vice versa. Other than hyperkalemia and GI disorders, the rate of adverse events for eplerenone is similar to that of placebo.
THERAPEUTIC USES. Spironolactone often is coadministered with thiazide or loop diuretics in the treatment of edema and hypertension. Such combinations result in increased mobilization of edema fluid while causing lesser perturbations of K+ homeostasis. Spironolactone is particularly useful in the treatment of resistant hypertension due to primary hyperaldosteronism (adrenal adenomas or bilateral adrenal hyperplasia) and of refractory edema associated with secondary aldosteronism (cardiac failure, hepatic cirrhosis, nephrotic syndrome, and severe ascites). Spironolactone is considered the diuretic of choice in patients with hepatic cirrhosis. Spironolactone, added to standard therapy, substantially reduces morbidity and mortality and ventricular arrhythmias in patients with heart failure (see Chapter 28). Clinical experience with eplerenone is limited. Eplerenone appears to be a safe and effective antihypertensive drug. In patients with acute myocardial infarction complicated by left ventricular systolic dysfunction, addition of eplerenone to optimal medical therapy significantly reduces morbidity and mortality.
INHIBITORS OF THE NONSPECIFIC CATION CHANNEL: ATRIAL NATRIURETIC PEPTIDES
Four natriuretic peptides are relevant with respect to human physiology: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and urodilatin. The inner medullary collecting duct (IMCD) is a major site of action of natriuretic peptides.
Three natriuretic peptides (NPs)—ANP, BNP, and CNP—share a common homologous 17-member amino acid ring formed by a disulfide bridge between cysteine residues, although they are products of different genes. Urodilatin, also structurally similar, arises from altered processing of the same precursor molecule as ANP and has 4 additional amino acids at the N terminus. ANP and BNP are produced by the heart in response to wall stretch, CNP is of endothelial and renal cell origin; urodilatin is found in the kidney and urine. NP receptors (NPRs), classified as types A, B and C, are membrane monospans. NPRA (binds ANP and BNP) and NPRB (binds CNP) have intracellular domains with guanylate cyclase activity and a protein kinase element. NPRC (binds all NPs) has a truncated intracellular domain and may help with NP clearance. The various NPs have somewhat overlapping effects, causing natriuresis, inhibition of production of renin and aldosterone, and vasodilation (the result of cyclic GMP elevation in vascular smooth muscle).
MECHANISM AND SITE OF ACTION. The IMCD is the final site along the nephron where Na+ is reabsorbed. Up to 5% of the filtered Na+ load can be reabsorbed here. The effects of NPs are mediated via effects of cyclic GMP on Na+ transporters (Figure 25–7). Two types of Na+ channels are expressed in IMCD. The first is an amiloride-sensitive, 28pS, nonselective, cyclic nucleotide gated cation (CNG) channel. This channel is inhibited by cGMP and by ANPs via their capacity to stimulate membrane-bound guanylyl cyclase activity and elevate cellular cGMP. The second type of Na+ channel expressed in the IMCD is the low-conductance 4 pS highly selective Na+ channel ENaC. The majority of Na+ reabsorption in the IMCD is mediated via the CNG channel.
Figure 25–7 Inner medullary collecting duct (IMCD) Na+ transport and its regulation. Na+ enters the IMCD cell in one of two ways: via epithelial Na+ channel (ENaC), and through a cyclic nucleotide gated nonspecific cation channel (CNGC) that transports Na+, K+, and NH4+ and is gated by cyclic GMP. Na+ then exits the cell via the Na+, K+-ATPase. The CNGC is the primary pathway for Na+ entry, and is inhibited by natriuretic peptides. Atrial natriuretic peptides (ANP) bind to surface receptors (natriuretic peptide receptors A, B, and C). The A and B receptors are isoforms of particulate guanylyl cyclase that synthesize cyclic GMP. Cyclic GMP inhibits the CNGC directly, and indirectly through PKG. PKG activation also inhibits Na+ exit via the Na+, K+-ATPase.
EFFECTS ON URINARY EXCRETION AND RENAL HEMODYNAMICS. Nesiritide (human recombinant BNP) inhibits Na+ transport in both the proximal and distal nephron but its primary effect is in the IMCD. Urinary Na+ excretion increases with nesiritide but the effect may be attenuated by upregulation of Na+ reabsorption in upstream segments of the nephron. GFR increases in response to nesiritide in normal subjects, but in treated patients with congestive heart failure GFR may increase, decrease, or remain unchanged.
OTHER ACTIONS. Administration of nesiritide decreases systemic and pulmonary resistances and left ventricular filling pressure, and induces a secondary increase in cardiac output.
ELIMINATION. Natriuretic peptides are administered intravenously. Nesiritide has a distribution t1/2 of 2 min and a mean terminal t1/2 of 18 min. There is no need to adjust the dose for renal insufficiency.
TOXICITY, ADVERSE EFFECTS, CONTRAINDICATIONS, DRUG INTERACTIONS. There are concerns about adverse renal effects and reports of increased short-term mortality in patients treated with nesiritide. Increases in serum creatinine concentration may be related to decreases in extracellular fluid volume, higher doses of diuretics used, decreases in blood pressure, and activation of the renin–angiotensin–aldosterone system. The Vasodilation in the Management of Acute CHF (VAMC) trial showed no increased risk with low or moderate doses of diuretics but an increased risk with high-dose diuretics (>160 mg furosemide), rising with increasing doses. Oral ACE inhibitors may increase the risk of hypotension with nesiritide. There are no data to suggest that nesiritide reduces mortality in the short term or long term in patients with acute decompensated CHF.
THERAPEUTIC USES. Human recombinant ANP (carperitide, available only in Japan) and BNP (nesiritide [NATRECOR]) are the available therapeutic agents of this class. Urodilatin (ularitide) is in development. Use of nesiritide should be limited to patients with acutely decompensated CHF with shortness of breath at rest; the drug should not be used in place of diuretics. Nesiritide reduces symptoms and improves hemodynamic parameters in those with dyspnea at rest who are not hypotensive.
CLINICAL USE OF DIURETICS
SITE AND MECHANISM OF DIURETIC ACTION. An understanding of the sites and mechanisms of action of diuretics enhances comprehension of the clinical aspects of diuretic pharmacology. Figure 25–5 provides a summary view of the sites and mechanisms of actions of diuretics.
THE ROLE OF DIURETICS IN CLINICAL MEDICINE. Figure 25–8 illustrates the 3 fundamental strategies for mobilizing edema fluid and provides a road map for treatment:
• Correction of the underlying disease
• Restriction of Na+ intake
• Administration of diuretics
Figure 25–9 presents a useful synthesis, Brater’s algorithm, a logically compelling algorithm for diuretic therapy (specific recommendations for drug, dose, route, and drug combinations) in patients with edema caused by renal, hepatic, or cardiac disorders.
Figure 25–9 “Brater’s algorithm” for diuretic therapy of chronic renal failure, nephrotic syndrome, congestive heart failure, and cirrhosis. Follow algorithm until adequate response is achieved. If adequate response is not obtained, advance to the next step. For illustrative purposes, the thiazide diuretic used is hydrochlorothiazide (HCTZ). An alternative thiazide-type diuretic may be substituted with dosage adjusted to be pharmacologically equivalent to the recommended dose of HCTZ. Do not combine 2 K+ -sparing diuretics due to the risk of hyperkalemia. CrCl indicates creatinine clearance in mL/min, and ceiling dose refers to the smallest dose of diuretic that produces a near-maximal effect. Ceiling doses of loop diuretics and dosing regimens for continuous intravenous infusions of loop diuretics are disease-state-specific. Doses are for adults only.
The clinical situation dictates whether a patient should receive diuretics and what therapeutic regimen should be used (type of diuretic, dose, route of administration, and speed of mobilization of edema fluid). Massive pulmonary edema in patients with acute left-sided heart failure is a medical emergency requiring rapid, aggressive therapy including intravenous administration of a loop diuretic. In this setting, use of oral diuretics is inappropriate. Conversely, mild pulmonary and venous congestion associated with chronic heart failure is best treated with an oral loop or thiazide diuretic, the dosage of which should be titrated carefully to maximize the benefit-to-risk ratio. Loop and thiazide diuretics decrease morbidity and mortality in heart failure patients: MR antagonists also demonstrate reduced morbidity and mortality in heart failure patients receiving optimal therapy with other drugs.
Periodic administration of diuretics to cirrhotic patients with ascites may eliminate the necessity for or reduce the interval between paracenteses, adding to patient comfort and sparing protein reserves that are lost during the paracenteses. Although diuretics can reduce edema associated with chronic renal failure, increased doses of more powerful loop diuretics usually are required. In nephrotic syndrome, diuretic response often is disappointing. In chronic renal failure and cirrhosis, edema will not pose an immediate health risk, but can greatly reduce quality of life. In such cases, only partial removal of edema fluid should be attempted, and fluid should be mobilized slowly using a diuretic regimen that accomplishes the task with minimal perturbation of normal physiology.
Diuretic resistance refers to edema that is or has become refractory to a given diuretic. If diuretic resistance develops against a less efficacious diuretic, a more efficacious diuretic should be substituted, such as a loop diuretic for a thiazide. However, resistance to loop diuretics can be due to several causes. NSAID coadministration is a common preventable cause of diuretic resistance. Prostaglandin production, especially PGE2, is an important counterregulatory mechanism in states of reduced renal perfusion such as volume contraction, congestive heart failure, and cirrhosis characterized by activation of the renin–angiotensin–aldosterone (RAA) and sympathetic nervous systems. NSAID administration can block these prostaglandin-mediated effects that counterbalance the RAA and sympathetic nervous system, resulting in salt and water retention. Diuretic resistance also occurs with COX-2-selective inhibitors.
In chronic renal failure, a reduction in RBF decreases delivery of diuretics to the kidney, and accumulation of endogenous organic acids competes with loop diuretics for transport at the proximal tubule. Consequently, diuretic concentration at the active site in the tubular lumen is diminished. In nephrotic syndrome, binding of diuretics to luminal albumin was postulated to limit response; however, the validity of this concept has been challenged. In hepatic cirrhosis, nephrotic syndrome, and heart failure, nephrons may have diminished diuretic responsiveness because of increased proximal tubular Na+reabsorption, leading to diminished Na+ delivery to distal nephron.
Faced with resistance to loop diuretics, the clinician has several options:
• Bed rest may restore drug responsiveness by improving the renal circulation.
• An increase in dose of loop diuretic may restore responsiveness; however, nothing is gained by increasing the dose above that which causes a near-maximal effect (the ceiling dose) of the diuretic.
• Administration of smaller doses more frequently or a continuous intravenous infusion of a loop diuretic will increase the length of time that an effective diuretic concentration is at the active site.
• Use of combination therapy to sequentially block more than 1 site in the nephron may result in a synergistic interaction between 2 diuretics. For example, a combination of a loop diuretic with a K+-sparing or a thiazide diuretic may improve therapeutic response; however, nothing is gained by the administration of 2 drugs of the same type. Thiazide diuretics with significant proximal tubular effects (e.g., metolazone) are particularly well suited for sequential blockade when coadministered with a loop diuretic.
• Reducing salt intake will diminish postdiuretic Na+ retention that can nullify previous increases in Na+ excretion.
• Scheduling of diuretic administration shortly before food intake will provide effective diuretic concentration in the tubular lumen when salt load is highest.
Arginine vasopressin (antidiuretic hormone or ADH in humans) is the main hormone that regulates body fluid osmolality. The hormone is released by the posterior pituitary whenever water deprivation causes an increased plasma osmolality or whenever the cardiovascular system is challenged by hypovolemia and/or hypotension. Vasopressin acts primarily in the renal collecting duct increasing the water permeability of the cell membrane, thus permitting water to move passively down an osmotic gradient across the collecting duct into the extracellular compartment.
Vasopressin is a potent vasopressor/vasoconstrictor. It is also a neurotransmitter; among its actions in the CNS are apparent roles in the secretion of adrenocorticotropic hormone (ACTH) and in regulation of the cardiovascular system, temperature, and other visceral functions. Vasopressin also promotes release of coagulation factors by vascular endothelium and increases platelet aggregability.
ANATOMY. The antidiuretic mechanism in mammals involves 2 anatomical components: a CNS component for synthesis, transport, storage, and release of vasopressin and a renal collecting-duct system composed of epithelial cells that respond to vasopressin by increasing their water permeability. The CNS component of the antidiuretic mechanism is called the hypothalamo-neurohypophyseal system and consists of neurosecretory neurons with perikarya located predominantly in 2 specific hypothalamic nuclei, the supraoptic nucleus (SON) and paraventricular nucleus (PVN). Long axons of magnocellular neurons in SON and PVN terminate in the neural lobe of the posterior pituitary (neurohypophysis), where they release vasopressin and oxytocin (see Figure 38–1).
SYNTHESIS. Vasopressin and oxytocin are synthesized mainly in the perikarya of magnocellular neurons in the SON and PVN. Parvicellular neurons in the PVN also synthesize vasopressin. Vasopressin synthesis appears to be regulated solely at the transcriptional level. In humans, a 168-amino acid preprohormone (Figure 25–10) is synthesized and then packaged into membrane-associated granules. The prohormone contains 3 domains: vasopressin (residues 1-9), vasopressin (VP)-neurophysin (residues 13-105), and VP-glycopeptide (residues 107-145). The vasopressin domain is linked to the VP-neurophysin domain through a GLY-LYS-ARG-processing signal, and the VP-neurophysin is linked to the VP-glycopeptide domain by an ARG-processing signal. In secretory granules, an endopeptidase, exopeptidase, monooxygenase, and lyase act sequentially on the prohormone to produce vasopressin, VP-neurophysin (sometimes referred to as neurophysin II), and VP-glycopeptide. The synthesis and transport of vasopressin depend on the preprohormone conformation. In particular, VP-neurophysin binds vasopressin and is critical to correct processing, transport, and storage of vasopressin. Genetic mutations in either the signal peptide or VP-neurophysin give rise to central diabetes insipidus.
Figure 25–10 Processing of human arginine vasopressin (AVP) preprohormone. More than 40 mutations in the single gene on chromosome 20 that encodes AVP preprohormone give rise to central diabetes insipidus. *Boxes indicate mutations leading to central diabetes insipidus.
VASOPRESSIN SYNTHESIS OUTSIDE THE CNS. Vasopressin also is synthesized by heart and adrenal gland. In the heart, elevated wall stress increases vasopressin synthesis several fold.
REGULATION OF VASOPRESSIN SECRETION. An increase in plasma osmolality is the principal physiological stimulus for vasopressin secretion by the posterior pituitary. Severe hypovolemia/hypotension also is a powerful stimulus for vasopressin release. In addition, pain, nausea, and hypoxia can stimulate vasopressin secretion, and several endogenous hormones and pharmacological agents can modify vasopressin release.
HYPEROSMOLALITY. The osmolality threshold for secretion is ~280 mOsm/kg. Below the threshold, vasopressin is barely detectable in plasma, and above the threshold, vasopressin levels are a steep and relatively linear function of plasma osmolality. Indeed, a 2% elevation in plasma osmolality causes a 2- to 3-fold increase in plasma vasopressin levels, which in turn causes increased solute-free water reabsorption, with an increase in urine osmolality. Increases in plasma osmolality above 290 mOsm/kg lead to an intense desire for water (thirst). Thus, the vasopressin system affords the organism longer thirst-free periods and, in the event that water is unavailable, allows the organism to survive longer periods of water deprivation. Above a plasma osmolality of ~290 mOsm/kg, plasma vasopressin levels exceed 5 pM. Since urinary concentration is maximal (~1200 mOsm/kg) when vasopressin levels exceed 5 pM, further defense against hypertonicity depends entirely on water intake rather than on decreases in water loss. See Figure 25–17 in the 12th edition of the parent text for more details.
HEPATIC PORTAL OSMORECEPTORS. An oral salt load activates hepatic portal osmoreceptors leading to increased vasopressin release. This mechanism augments plasma vasopressin levels even before the oral salt load increases plasma osmolality.
HYPOVOLEMIA AND HYPOTENSION. Vasopressin secretion is regulated hemodynamically by changes in effective blood volume and/or arterial blood pressure. Regardless of the cause (e.g., hemorrhage, Na+ depletion, diuretics, heart failure, hepatic cirrhosis with ascites, adrenal insufficiency, or hypotensive drugs), reductions in effective blood volume and/or arterial blood pressure are associated with high circulating vasopressin concentrations. However, unlike osmoregulation, hemodynamic regulation of vasopressin secretion is exponential; i.e., small decreases (5%) in blood volume and/or pressure have little effect on vasopressin secretion, whereas larger decreases (20-30%) can increase vasopressin levels to 20-30 times normal (exceeding the vasopressin concentration required to induce maximal antidiuresis). Vasopressin is one of the most potent vasoconstrictors known, and the vasopressin response to hypovolemia or hypotension serves as a mechanism to stave off cardiovascular collapse during periods of severe blood loss and/or hypotension. Hemodynamic regulation of vasopressin secretion does not disrupt osmotic regulation; rather, hypovolemia/hypotension alters the set point and slope of the plasma osmolality-plasma vasopressin relationship (Figure 25–11).
Figure 25–11 Interactions between osmolality and hypovolemia/hypotension. Numbers in circles refer to percentage increase (+) or decrease (-) in blood volume or arterial blood pressure. N indicates normal blood volume/blood pressure. (Reprinted by permission from Macmillan Publishers Ltd: Robertson GL, Shelton RL, Athar S, The osmoregulation of vasopressin. Kidney Int, 1976;10:25, Copyright 1976.)
Neuronal pathways that mediate hemodynamic regulation of vasopressin release are different from those involved in osmoregulation. Baroreceptors in left atrium, left ventricle, and pulmonary veins sense blood volume (filling pressures), and baroreceptors in carotid sinus and aorta monitor arterial blood pressure. Nerve impulses reach brainstem nuclei predominantly through the vagal trunk and glossopharyngeal nerve; these signals are ultimately relayed to the SON and PVN.
HORMONES AND NEUROTRANSMITTERS. Vasopressin-synthesizing magnocellular neurons have a large array of receptors on both perikarya and nerve terminals; therefore, vasopressin release can be accentuated or attenuated by chemical agents acting at both ends of the magnocellular neuron. Also, hormones and neurotransmitters can modulate vasopressin secretion by stimulating or inhibiting neurons in nuclei that project, either directly or indirectly, to the SON and PVN. Because of these complexities, modulation of vasopressin secretion by most hormones or neurotransmitters is unclear. Several agents stimulate vasopressin secretion, including acetylcholine (by nicotinic receptors), histamine (by H1 receptors), dopamine (by both D1 and D2 receptors), glutamine, aspartate, cholecystokinin, neuropeptide Y, substance P, vasoactive intestinal polypeptide, prostaglandins, and angiotensin II (AngII). Inhibitors of vasopressin secretion include ANP, γ-aminobutyric acid, and opioids (particularly dynorphin via κ receptors). The affects of AngII have received the most attention. AngII synthesized in the brain and circulating AngII may stimulate vasopressin release. Inhibition of the conversion of AngII to AngIII blocks AngII-induced vasopressin release, suggesting that AngIII is the main effector peptide of the brain renin–angiotensin system controlling vasopressin release.
PHARMACOLOGICAL AGENTS. A number of drugs alter urine osmolality by stimulating or inhibiting vasopressin secretion. In most cases the mechanism is not known. Stimulators of vasopressin secretion include vincristine, cyclophosphamide, tricyclic antidepressants, nicotine, epinephrine, and high doses of morphine. Lithium, which inhibits the renal effects of vasopressin, also enhances vasopressin secretion. Inhibitors of vasopressin secretion include ethanol, phenytoin, low doses of morphine, glucocorticoids, fluphenazine, haloperidol, promethazine, oxilorphan, and butorphanol. Carbamazepine has a renal action to produce antidiuresis in patients with central diabetes insipidus but actually inhibits vasopressin secretion by a central action.
VASOPRESSIN RECEPTORS. Cellular vasopressin effects are mediated mainly by interactions of the hormone with the 3 types of receptors, V1a, V1b, and V2. All are GPCRs.
The V1a receptor is the most widespread subtype of vasopressin receptor; it is found in vascular smooth muscle, adrenal gland, myometrium, bladder, adipocytes, hepatocytes, platelets, renal medullary interstitial cells, vasa recta in the renal microcirculation, epithelial cells in the renal cortical collecting-duct, spleen, testis, and many CNS structures. V1b receptors have a more limited distribution and are found in the anterior pituitary, several brain regions, pancreas, and adrenal medulla. V2 receptors are located predominantly in principal cells of the renal collecting-duct system but also are present on epithelial cells in TAL and on vascular endothelial cells.
V1 RECEPTOR-EFFECTOR COUPLING. Figure 25–12 summarizes the current model of V1 receptor-effector coupling. Vasopressin binding to V1 receptors activates the Gq-PLC-IP3 pathway, thereby mobilizing intracellular Ca2+ and activating PKC, ultimately causing biological effects that include immediate responses (e.g., vasoconstriction, glycogenolysis, platelet aggregation, and ACTH release) and growth responses in smooth muscle cells.
Figure 25–12 Mechanism of V1receptor-effector coupling. Binding of AVP to V1 vasopressin receptors (V1) stimulates membrane-bound phospholipases. Stimulation of the Gq activates the PLCv-IP3/DAG-Ca2+-PKC pathway. Activation of V1 receptors also causes influx of extracellular Ca2+ by an unknown mechanism. PKC and Ca2+/calmodulin-activated protein kinases phosphorylate cell-type-specific proteins leading to cellular responses. A further component of the AVP response derives from the production of eicosanoids secondary to the activation of PLA2; the resulting mobilization of arachidonic acid (AA) provides substrate for eicosanoid synthesis by the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, leading to local production of prostaglandins (PG), thromboxanes (TX), and leukotrienes (LT), which may activate myriad signaling pathways, including those linked to GS and Gq.
V2 RECEPTOR-EFFECTOR COUPLING. Principal cells in renal collecting duct have V2 receptors on their basolateral membranes that couple to GS to stimulate adenylyl cyclase activity (Figure 25–13). When vasopressin binds to V2 receptors, the resulting activation of the cyclic AMP/PKA pathway triggers an increased rate of insertion of water channel-containing vesicles (WCVs) into the apical membrane and a decreased rate of endocytosis of WCVs from the apical membrane. Because WCVs contain preformed functional water channels (aquaporin 2), their net shift into apical membranes in response to V2 receptor stimulation greatly increases water permeability of the apical membrane (see Figures 25–13and 25–14).
Figure 25–13 Mechanism of V2 receptor-effector coupling. Binding of vasopressin (AVP) to the V2 receptor activates the GS-adenylyl cyclase-cAMP-PKA pathway and shifts the balance of aquaporin 2 trafficking toward the apical membrane of the principal cell of the collecting duct, thus enhancing water permeability. Although phosphorylation of Ser256 of aquaporin 2 is involved in V2 receptor signaling, other proteins located both in the water channel-containing vesicles and the apical membrane of the cytoplasm also may be involved.
Figure 25–14 Structure of aquaporins. Aquaporins have 6 transmembrane domains, and the NH2 and COOH termini are intracellular. Loops B and E each contain an asparagine-proline-alanine (NPA) sequence. Aquaporins fold with transmembrane domains 1, 2, and 6 in close proximity and transmembrane domains 3, 4 and 5 in juxtaposition. The long B and E loops dip into the membrane, and the NPA sequences align to create a pore through which water can diffuse. Most likely aquaporins form a tetrameric oligomer. At least 7 aquaporins are expressed at distinct sites in the kidney. Aquaporin 1, abundant in the proximal tubule and descending thin limb, is essential for concentration of urine. Aquaporin 2, exclusively expressed in the principal cells of the connecting tubule and collecting duct, is the major vasopressin-regulated water channel. Aquaporin 3 and aquaporin 4 are expressed in the basolateral membranes of collecting-duct principal cells and provide exit pathways for water reabsorbed apically by aquaporin 2. Aquaporin 7 is in the apical brush border of the straight proximal tubule. Aquaporins 6-8 are also expressed in kidney; their functions remain to be clarified. Vasopressin regulates water permeability of the collecting duct by influencing the trafficking of aquaporin 2 from intracellular vesicles to the apical plasma membrane (Figure 25–13). AVP-induced activation of the cAMP-PKA pathway also enhances expression of aquaporin 2 mRNA and protein; chronic dehydration thus causes upregulation of aquaporin 2 and water transport in the collecting duct.
V2-receptor activation also increases urea permeability by 400% in the terminal portions of the IMCD. V2 receptors increase urea permeability by activating a vasopressin-regulated urea transporter (termedVRUT, UT1, or UTA1), most likely by PKA-induced phosphorylation. Kinetics of vasopressin-induced water and urea permeability differ, and vasopressin-induced regulation of VRUT does not entail vesicular trafficking to the plasma membrane.
V2-receptor activation also increases Na+ transport in TAL and collecting duct. Increased Na+ transport in TAL is mediated by 3 mechanisms that affect the Na+-K+-2C1– symporter: rapid phosphorylation of the symporter, translocation of the symporter into the luminal membrane, and increased expression of symporter protein. Enhanced Na+ transport in collecting duct is mediated by increased expression of subunits of the epithelial Na+ channel. The multiple mechanisms by which vasopressin increases water reabsorption are summarized in Figure 25–15.
Figure 25–15 Mechanisms by which vasopressin increases the renal conservation of water. Red and black arrows denote major and minor pathways, respectively. IMCD, inner medullary collecting duct; TAL, thick ascending limb; VRUT, vasopressin-regulated urea transporter.
RENAL ACTIONS OF VASOPRESSIN. Several sites of vasopressin action in kidney involve both V1 and V2 receptors (see Figure 25–15).
V1 receptors mediate contraction of mesangial cells in the glomerulus and contraction of vascular smooth muscle cells in vasa recta and efferent arteriole. V1-receptor-mediated reduction of inner medullary blood flow contributes to the maximum concentrating capacity of the kidney. V1 receptors also stimulate prostaglandin synthesis by medullary interstitial cells. Since PGE2 inhibits adenylyl cyclase in collecting duct, stimulation of prostaglandin synthesis by V1 receptors may counterbalance V2-receptor-mediated antidiuresis. V1receptors on principal cells in cortical collecting duct may inhibit V2-receptor-mediated water flux by activation of PKC. V2 receptors mediate the most prominent response to vasopressin, which is increased water permeability of the collecting duct at concentrations as low as 50 fM. Thus, V2-receptor-mediated effects of vasopressin occur at concentrations far lower than are required to engage V1-receptor-mediated actions. Other renal actions mediated by V2 receptors include increased urea transport in IMCD and increased Na+transport in TAL; both effects contribute to the urine-concentrating ability of the kidney. V2 receptors also increase Na+ transport in cortical collecting duct, and this may synergize with aldosterone to enhance Na+ reabsorption during hypovolemia.
PHARMACOLOGICAL MODIFICATION OF THE ANTIDIURETIC RESPONSE TO VASOPRESSIN. NSAIDs, particularly indomethacin, enhance the antidiuretic response to vasopressin. Because prostaglandins attenuate antidiuretic responses to vasopressin and NSAIDs inhibit prostaglandin synthesis, reduced prostaglandin production probably accounts for potentiation of vasopressin’s antidiuretic response. Carbamazepine and chlorpropamide also enhance antidiuretic effects of vasopressin by unknown mechanisms. In rare instances, chlorpropamide can induce water intoxication. A number of drugs inhibit the antidiuretic actions of vasopressin. Lithium is of particular importance because of its use in the treatment of manic-depressive disorders. Acutely, Li+ appears to reduce V2-receptor-mediated stimulation of adenylyl cyclase. Also, Li+ increases plasma levels of PTH, a partial antagonist to vasopressin. In most patients, the antibiotic demeclocycline attenuates the antidiuretic effects of vasopressin, probably owing to decreased accumulation and action of cyclic AMP.
NONRENAL ACTIONS OF VASOPRESSIN
Cardiovascular System. The cardiovascular effects of vasopressin are complex. Vasopressin is a potent vasoconstrictor (V1 receptor-mediated), and resistance vessels throughout the circulation may be affected. Vascular smooth muscle in the skin, skeletal muscle, fat, pancreas, and thyroid gland appears most sensitive, with significant vasoconstriction also occurring in GI tract, coronary vessels, and brain. Despite the potency of vasopressin as a direct vasoconstrictor, vasopressin-induced pressor responses in vivo are minimal and occur only with vasopressin concentrations significantly higher than those required for maximal antidiuresis. To a large extent, this is due to circulating vasopressin actions on V1 receptors to inhibit sympathetic efferents and potentiate baroreflexes. In addition, V2 receptors cause vasodilation in some blood vessels.
Vasopressin helps to maintain arterial blood pressure during episodes of severe hypovolemia/hypotension. The effects of vasopressin on heart (reduced cardiac output and heart rate) are largely indirect and result from coronary vasoconstriction, decreased coronary blood flow, and alterations in vagal and sympathetic tone. Some patients with coronary insufficiency experience angina even in response to the relatively small amounts of vasopressin required to control diabetes insipidus, and vasopressin-induced myocardial ischemia has led to severe reactions and even death.
CNS. Vasopressin likely plays a role as a neurotransmitter and/or neuromodulator. Although vasopressin can modulate CNS autonomic systems controlling heart rate, arterial blood pressure, respiration rate, and sleep patterns, the physiological significance of these actions is unclear. While vasopressin is not the principal corticotropin-releasing factor, vasopressin may provide for sustained activation of the hypothalamic-pituitary-adrenal axis during chronic stress. CNS effects of vasopressin appear to be mediated predominantly by V1 receptors.
Blood Coagulation. Activation of V2 receptors by desmopressin or vasopressin increases circulating levels of procoagulant factor VIII and of von Willebrand factor. These effects are mediated by extrarenal V2 receptors. Presumably, vasopressin stimulates secretion of von Willebrand factor and of factor VIII from storage sites in vascular endothelium. However, since release of von Willebrand factor does not occur when desmopressin is applied directly to cultured endothelial cells or to isolated blood vessels, intermediate factors are likely to be involved.
Other Nonrenal Effects of Vasopressin. At high concentrations, vasopressin stimulates smooth muscle contraction in uterus (by oxytocin receptors) and GI tract (by V1 receptors). Vasopressin is stored in platelets, and activation of V1 receptors stimulates platelet aggregation. Also, activation of V1 receptors on hepatocytes stimulates glycogenolysis.
VASOPRESSIN RECEPTOR AGONISTS AND ANTAGONISTS
A number of vasopressin-like peptides occur naturally across the animal kingdom (Table 25–8); all are nonapeptides. In all mammals except swine, the neurohypophyseal peptide is 8-arginine vasopressin, and the terms vasopressin, arginine vasopressin (AVP), and ADH are used interchangeably. There are also a number of synthetic peptides with receptor-subtype specificity, and 1 non-peptide agonist.
Vasopressin Receptor Agonists
Many vasopressin analogs were synthesized with the goal of increasing duration of action and selectivity for vasopressin receptor subtypes (V1 versus V2 receptors, which mediate pressor responses and antidiuretic responses, respectively). Thus, the antidiuretic-to-vasopressor ratio for the V2–selective agonist, 1-deamino-8-D-arginine vasopressin, also called desmopressin (DDAVP, MINIRIN, STIMATE), is ~3000 times greater than that for vasopressin, and is the preferred drug for the treatment of central diabetes insipidus. Substitution of valine for glutamine in position 4 further increases the antidiuretic selectivity, and the antidiuretic to vasopressor ratio for deamino [Val4, D-Arg8]AVP is] ~11,000 times greater than that for vasopressin.
Increasing V1 selectivity has proved more difficult than increasing V2 selectivity. Vasopressin receptors in the adenohypophysis that mediate vasopressin-induced ACTH release are neither classical V1 nor V2 receptors. Because vasopressin receptors in the adenohypophysis appear to share a common signal-transduction mechanism with classical V1 receptors, and since many vasopressin analogs with vasoconstrictor activity release ACTH, V1 receptors have been subclassified into V1a (vascular/hepatic) and V1b (pituitary) receptors (also called V3 receptors). There are selective agonists for V1a and V1breceptors.
The chemical structure of oxytocin is closely related to that of vasopressin: oxytocin is [Ile3, Leu8]AVP. With such structural similarities, it is not surprising that vasopressin and oxytocin agonists and antagonists can bind to each other’s receptors. Therefore, most of the available peptide vasopressin agonists and antagonists have some affinity for oxytocin receptors; at high doses, they may block or mimic the effects of oxytocin.
DISEASES AFFECTING THE VASOPRESSIN SYSTEM
DIABETES INSIPIDUS (DI). DI is a disease of impaired renal water conservation owing either to inadequate vasopressin secretion from the neurohypophysis (central DI) or to insufficient renal vasopressin response (nephrogenic DI). Very rarely, DI can be caused by an abnormally high degradation rate of vasopressin by circulating vasopressinases. Pregnancy may accentuate or reveal central and/or nephrogenic DI by increasing plasma levels of vasopressinase and by reducing renal sensitivity to vasopressin. Patients with DI excrete large volumes (>30 mL/kg per day) of dilute (>200 mOsm/kg) urine and, if their thirst mechanism is functioning normally, are poly-dipsic. Central DI can be distinguished from nephrogenic DI by administration of desmopressin, which will increase urine osmolality in patients with central DI but have little or no effect in patients with nephrogenic DI. DI can be differentiated from primary polydipsia by measuring plasma osmolality, which will be low to low-normal in patients with primary polydipsia and high to high-normal in patients with DI.
CENTRAL DI. Head injury, either surgical or traumatic, in the region of the pituitary and/or hypothalamus may cause central DI. Postoperative central DI may be transient, permanent, or triphasic (recovery followed by permanent relapse). Other causes include hypothalamic or pituitary tumors, cerebral aneurysms, CNS ischemia, and brain infiltrations and infections. Central DI may also be idiopathic or familial. Familial central DI usually is autosomal dominant (chromosome 20), and vasopressin deficiency occurs several months or years after birth and worsens gradually. Autosomal dominant central DI is linked to mutations in the vasopressin preprohormone gene that cause the prohormone to misfold and oligomerize improperly. Accumulation of mutant vasopressin precursor causes neuronal death, hence the dominant mode of inheritance. Rarely, familial central DI is autosomal recessive owing to a mutation in the vasopressin peptide itself that gives rise to an inactive vasopressin mutant.
Antidiuretic peptides are the primary treatment for central DI, with desmopressin being the peptide of choice. For patients with central DI who cannot tolerate antidiuretic peptides because of side effects or allergic reactions, other treatment options are available. Chlorpropamide, an oral sulfonylurea, potentiates the action of small or residual amounts of circulating vasopressin and will reduce urine volume in more than half of all patients with central DI. Doses of 125-500 mg daily appear effective in patients with partial central DI. If polyuria is not controlled satisfactorily with chlorpropamide alone, addition of a thiazide diuretic to the regimen usually results in an adequate reduction in urine volume. Carbamazepine (800-1000 mg daily in divided doses) also reduces urine volume in patients with central DI. Long-term use may induce serious adverse effects; therefore, carbamazepine is used rarely to treat central DI. These agents are not effective in nephrogenic DI, which indicates that functional V2 receptors are required for the antidiuretic effect. Because carbamazepine inhibits and chlorpropamide has little effect on vasopressin secretion, it is likely that carbamazepine and chlorpropamide act directly on the kidney to enhance V2-receptor-mediated antidiuresis.
NEPHROGENIC DI. Nephrogenic DI may be congenital or acquired. Hypercalcemia, hypokalemia, postobstructive renal failure, Li+, foscarnet, clozapine, demeclocycline, and other drugs can induce nephrogenic DI. As many as 1 in 3 patients treated with Li+ may develop nephrogenic DI. X-linked nephrogenic DI is caused by mutations in the gene encoding the V2 receptor, which maps to Xq28. Mutations in the V2-receptor gene may cause impaired routing of the V2 receptor to the cell surface, defective coupling of the receptor to G proteins, or decreased receptor affinity for vasopressin. Autosomal recessive and dominant nephrogenic DI result from inactivating mutations in aquaporin 2. These findings indicate that aquaporin 2 is essential for the antidiuretic effect of vasopressin in humans.
Although the mainstay of treatment of nephrogenic DI is assurance of an adequate water intake, drugs also can be used to reduce polyuria. Amiloride blocks Li+ uptake by the Na+ channel in the collecting-duct system and may be effective in patients with mild to moderate concentrating defects. Thiazide diuretics reduce the polyuria of patients with DI and often are used to treat nephrogenic DI. In infants with nephrogenic DI, use of thiazides may be crucial because uncontrolled polyuria may exceed the child’s capacity to imbibe and absorb fluids. It is possible that the natriuretic action of thiazides and resulting extracellular fluid volume depletion play an important role in thiazide-induced antidiuresis. The antidiuretic effects appear to parallel the thiazide’s ability to cause natriuresis, and the drugs are given in doses similar to those used to mobilize edema fluid. In patients with DI, a 50% reduction of urine volume is a good response to thiazides. Moderate restriction of Na+ intake can enhance the antidiuretic effectiveness of thiazides.
A number of case reports describe the effectiveness of indomethacin in the treatment of nephrogenic DI; however, other prostaglandin synthase inhibitors (e.g., ibuprofen) appear to be less effective. The mechanism of the effect may involve a decrease in GFR, an increase in medullary solute concentration, and/or enhanced proximal fluid reabsorption. Also, because prostaglandins attenuate vasopressin-induced antidiuresis in patients with at least a partially intact V2-receptor system, some of the antidiuretic response to indomethacin may be due to diminution of the prostaglandin effect and enhancement of vasopressin effects on the principal cells of collecting duct.
SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE (SIADH). SIADH is a disease of impaired water excretion with accompanying hyponatremia and hypoosmolality caused by the inappropriate secretion of vasopressin. Clinical manifestations of plasma hypotonicity resulting from SIADH may include lethargy, anorexia, nausea and vomiting, muscle cramps, coma, convulsions, and death. A multitude of disorders can induce SIADH, including malignancies, pulmonary diseases, CNS injuries/diseases (e.g., head trauma, infections, and tumors), and general surgery.
Three drug classes are commonly implicated in drug-induced SIADH: psychotropic medications (e.g., selective serotonin reuptake inhibitors, haloperidol, and tricyclic antidepressants), sulfonylureas (e.g., chlorpropamide), and vinca alkaloids (e.g., vincristine and vinblastine). Other drugs strongly associated with SIADH include clonidine, cyclophosphamide, enalapril, felbamate, ifosfamide, and methyldopa, pentamidine, and vinorelbine. In a normal individual, an elevation in plasma vasopressin per se does not induce plasma hypotonicity because the person simply stops drinking owing to an osmotically induced aversion to fluids. Therefore, plasma hypotonicity only occurs when excessive fluid intake (oral or intravenous) accompanies inappropriate secretion of vasopressin. Treatment of hypotonicity in the setting of SIADH includes water restriction, intravenous administration of hypertonic saline, loop diuretics (which interfere with kidney’s concentrating ability), and drugs that inhibit the effect of vasopressin to increase water permeability in collecting ducts. To inhibit vasopressin’s action in collecting ducts, demeclocycline, a tetracycline, has been the preferred drug, but tolvaptan and conivaptan, V2 receptor antagonists, are now available (see next section and Table 25–9).
Vasopressin Receptor Antagonists
Although Li+ can inhibit the renal actions of vasopressin, it is effective in only a minority of patients, may induce irreversible renal damage when used chronically, and has a low therapeutic index. Therefore, Li+ should be considered for use only in patients with symptomatic SIADH who cannot be controlled by other means or in whom tetracyclines are contraindicated (e.g., patients with liver disease). It is important to stress that the majority of patients with SIADH do not require therapy because plasma Na+ stabilizes in the range of 125-132 mM; such patients usually are asymptomatic. Only when symptomatic hypotonicity ensues, generally when plasma Na+ levels drop below 120 mM, should therapy with demeclocycline be initiated. Since hypotonicity, which causes an influx of water into cells with resulting cerebral swelling, is the cause of symptoms, the goal of therapy is simply to increase plasma osmolality toward normal.
OTHER WATER-RETAINING STATES. In patients with congestive heart failure, cirrhosis, or nephrotic syndrome, effective blood volume often is reduced, and hypovolemia frequently is exacerbated by the liberal use of diuretics. Because hypovolemia stimulates vasopressin release, patients may become hyponatremic owing to vasopressin-mediated retention of water. The development of potent orally active V2 receptor antagonists and specific inhibitors of water channels in the collecting duct has provided a new therapeutic strategy not only in patients with SIADH but also in the more common setting of hyponatremia in patients with heart failure, liver cirrhosis, and nephrotic syndrome.
CLINICAL USE OF VASOPRESSIN PEPTIDES
Two antidiuretic peptides are available for clinical use in the U.S.:
• Vasopressin (synthetic 8-L-arginine vasopressin; PITRESSIN, others) is available as a sterile aqueous solution; it may be administered subcutaneously, intramuscularly, or intranasally.
• Desmopressin acetate (synthetic 1-deamino-8-D-arginine vasopressin; DDAVP, others) is available as a sterile aqueous solution packaged for intravenous or subcutaneous injection, in a solution for intranasal administration with either a nasal spray pump or rhinal tube delivery system, and in tablets for oral administration.
THERAPEUTIC USES. The therapeutic uses of vasopressin and its congeners can be divided into 2 main categories according to the vasopressin receptor involved.
V1 receptor-mediated therapeutic applications are based on the rationale that V1 receptors cause GI and vascular smooth muscle contraction. Vasopressin is the main agent used.
V1 receptor-mediated GI smooth muscle contraction has been used to treat postoperative ileus and abdominal distension and to dispel intestinal gas before abdominal roentgenography to avoid interfering gas shadows. V1 receptor-mediated vasoconstriction of the splanchnic arterial vessels reduces blood flow to the portal system and, thereby, attenuates pressure and bleeding in esophageal varices. Although endoscopic variceal banding ligation is the treatment of choice for bleeding esophageal varices, V1 receptor agonists have been used in an emergency setting until endoscopy can be performed. Simultaneous administration of nitroglycerin with V1 receptor agonists may attenuate the cardiotoxic effects of V1 agonists while enhancing their beneficial splanchnic effects. Also, V1 receptor agonists have been used during abdominal surgery in patients with portal hypertension to diminish the risk of hemorrhage during the procedure. Finally, V1 receptor-mediated vasoconstriction has been used to reduce bleeding during acute hemorrhagic gastritis, burn wound excision, cyclophosphamide-induced hemorrhagic cystitis, liver transplant, cesarean section, and uterine myoma resection.
The applications of V1 receptor agonists can be accomplished with vasopressin; however, the use of vasopressin for all these indications is no longer recommended because of significant adverse reactions. Terlipressin (LUCASSIN) is preferred for bleeding esophageal varices because of increased safety compared with vasopressin and is designated as an orphan drug for this use. Moreover, terlipressin is effective in patients with hepatorenal syndrome, particularly when combined with albumin. Terlipressin has been granted priority review, orphan drug status, and fast-track designation by the FDA for type I hepatorenal syndrome. Vasopressin levels in patients with vasodilatory shock are inappropriately low, and such patients are extraordinarily sensitive to the pressor actions of vasopressin. The combination of vasopressin and norepinephrine is superior to norepinephrine alone in the management of catecholamine-resistant vasodilatory shock. However, recent clinical trials show that, in comparison to catecholamines alone, addition of vasopressin does not improve outcomes in either cardiac arrest or septic shock.
V2 receptor-mediated therapeutic applications are based on the rationale that V2 receptors cause water conservation and release of blood coagulation factors. Desmopressin is the standard drug of choice.
Central but not nephrogenic DI can be treated with V2 receptor agonists, and polyuria and polydipsia usually are well controlled by these agents. Some patients experience transient DI (e.g., in head injury or surgery in the area of the pituitary); however, therapy for most patients with DI is lifelong. Desmopressin is the drug of choice for the vast majority of patients. The duration of effect from a single intranasal dose is from 6-20 h; twice-daily administration is effective in most patients. The usual intranasal dosage in adults is 10-40 μg daily either as a single dose or divided into 2 or 3 doses. In view of the high cost of the drug and the importance of avoiding water intoxication, the schedule of administration should be adjusted to the minimal amount required. In some patients, chronic allergic rhinitis or other nasal pathology may preclude reliable peptide absorption following nasal administration. Oral administration of desmopressin in doses 10-20 times the intranasal dose provides adequate desmopressin blood levels to control polyuria. Subcutaneous administration of 1-2 μg daily of desmopressin also is effective in central DI.
Vasopressin has little, if any, place in the long-term therapy of DI because of its short duration of action and V1 receptor-mediated side effects. Vasopressin can be used as an alternative to desmopressin in the initial diagnostic evaluation of patients with suspected DI and to control polyuria in patients with DI who recently have undergone surgery or experienced head trauma. Under these circumstances, polyuria may be transient, and long-acting agents may produce water intoxication.
Desmopressin is used in bleeding disorders. In most patients with type I von Willebrand disease (vWD) and in some with type IIn vWD, desmopressin will elevate von Willebrand factor and shorten bleeding time. However, desmopressin generally is ineffective in patients with types IIa, IIb, and III vWD. Desmopressin may cause a marked transient thrombocytopenia in individuals with type IIb vWD and is contraindicated in such patients. Desmopressin also increases factor VIII levels in patients with mild to moderate hemophilia A. Desmopressin is not indicated in patients with severe hemophilia A, those with hemophilia B, or those with factor VIII antibodies. In patients with renal insufficiency, desmopressin shortens bleeding time and increases circulating levels of factor VIII coagulant activity, factor VIII-related antigen, and ristocetin cofactor. It also induces the appearance of larger von Willebrand factor multimers. Desmopressin is effective in some patients with liver cirrhosis- or drug-induced (e.g., heparin, hirudin, and antiplatelet agents) bleeding disorders. Desmopressin, given intravenously at a dose of 0.3 μg/kg, increases factor VIII and von Willebrand factor for μ6 h. Desmopressin can be given at intervals of 12-24 h depending on the clinical response and severity of bleeding. Tachyphylaxis to desmopressin usually occurs after several days (owing to depletion of factor VIII and von Willebrand factor storage sites) and limits its usefulness to preoperative preparation, postoperative bleeding, excessive menstrual bleeding, and emergency situations.
Another V2 receptor-mediated therapeutic application is the use of desmopressin for primary nocturnal enuresis. Bedtime administration of desmopressin intranasal spray or tablets provides a high response rate that is sustained with long-term use, that is safe, and that accelerates the cure rate. Desmopressin also relieves post-lumbar puncture headache, probably by causing water retention and thereby facilitating rapid fluid equilibration in the CNS.
PHARMACOKINETICS. When vasopressin and desmopressin are given orally, they are inactivated quickly by trypsin. Inactivation by peptidases in various tissues (particularly liver and kidney) results in a plasma t1/2 of vasopressin of 17-35 min. Following intramuscular or subcutaneous injection, antidiuretic effects of vasopressin last 2-8 h.
TOXICITY, ADVERSE EFFECTS, CONTRAINDICATIONS, DRUG INTERACTIONS. Most adverse effects are mediated through V1 receptor activation on vascular and GI smooth muscle; such adverse effects are much less common and less severe with desmopressin than with vasopressin. After injection of large doses of vasopressin, marked facial pallor owing to cutaneous vasoconstriction is observed commonly. Increased intestinal activity is likely to cause nausea, belching, cramps, and an urge to defecate. Vasopressin should be administered with extreme caution in individuals suffering from vascular disease, especially coronary artery disease. Other cardiac complications include arrhythmia and decreased cardiac output. Peripheral vasoconstriction and gangrene were encountered in patients receiving large doses of vasopressin.
The major V2 receptor-mediated adverse effect is water intoxication. Many drugs, including carbamazepine, chlorpropamide, morphine, tricyclic antidepressants, and NSAIDs, can potentiate the antidiuretic effects of these peptides. Several drugs such as Li+, demeclocycline, and ethanol can attenuate the antidiuretic response to desmopressin. Desmopressin and vasopressin should be used cautiously in disease states in which a rapid increase in extracellular water may impose risks (e.g., in angina, hypertension, and heart failure) and should not be used in patients with acute renal failure. Patients receiving desmopressin to maintain hemostasis should be advised to reduce fluid intake. Also, it is imperative that these peptides not be administered to patients with primary or psychogenic polydipsia because severe hypotonic hyponatremia will ensue. Mild facial flushing and headache are the most common adverse effects. Allergic reactions ranging from urticaria to anaphylaxis may occur with desmopressin or vasopressin. Intranasal administration may cause local adverse effects in the nasal passages, such as edema, rhinorrhea, congestion, irritation, pruritus, and ulceration.
VASOPRESSIN RECEPTOR ANTAGONISTS
Table 25–9 summarizes selectivity of vasopressin receptor antagonists.
THERAPEUTIC USES. When the kidney perceives the arterial blood volume to be low (as in the disease states of CHF, cirrhosis, and nephrosis), AVP perpetuates a state of total body salt and water excess. V2 receptor (V2R) antagonists or “aquaretics” may have a therapeutic role in these conditions, especially in patients with concomitant hyponatremia. They are also effective in hyponatremia associated with SIADH. Aquaretics increase renal free water excretion with little or no change in electrolyte excretion. Since they do not affect Na+ reabsorption they do not stimulate the TGF mechanism with its associated consequence of reducing GFR.
Mozavaptan. Mozavaptan causes a dose-dependent increase in free water excretion with only slight increases in urinary Na+ and K+ excretion. Mozavaptan is available in 30-mg tablets. Its peak effects occur 60-90 min after an oral dose. Mozavaptan’s major side effects are dry mouth and abnormal liver function tests.
Tolvaptan. Tolvaptan (SAMSCA) is a selective oral V2R antagonist. Tolvaptan is approved for clinically significant hypervolemic and euvolemic hyponatremia. The drug is labeled with a black box warning against too rapid correction of hyponatremia (can have serious and fatal consequences) and the recommendation to initiate therapy in a hospital setting capable of close monitoring of serum Na+. Tolvaptan is contraindicated in patients receiving drugs that inhibit CYP3A4.
Tolvaptan is available in 15 and 30 mg tablets. Tolvaptan is 29 times more selective for the V2R than the V1aR. Tolvaptan has a t1/2 of 6-8 h and <1% is excreted in the urine. Tolvaptan is a substrate and inhibitor of P-glycoprotein and is eliminated entirely by CYP3A metabolism. Plasma concentrations of the drug are increased by ketoconazole. Adverse effects include GI effects, hyperglycemia, and pyrexia. Less common are cerebrovascular accident, deep vein thrombosis, disseminated intravascular coagulation, intracardiac thrombus, ventricular fibrillation, urethral hemorrhage, vaginal hemorrhage, pulmonary embolism, respiratory failure, diabetic ketoacidosis, ischemic colitis, increase in prothrombin time, and rhabdomyolysis.
Conivaptan. Conivaptan (VAPRISOL) is a nonselective V1aR/V2R antagonist that is FDA-approved for the treatment of hospitalized patients with euvolemic hyponatremia and hypervolemic hyponatremia. The drug is available only for intravenous infusion. In CHF patients, conivaptan increases renal free water excretion without a change in systemic vascular resistance.
Conivaptan is highly protein bound, has a terminal elimination t1/2 of 5-12 h, is metabolized via CYP3A4, and is partially excreted by the kidney. Caution should be exercised in those with hepatic and renal disease. At higher doses clearance may be reduced in the elderly. Conivaptan should not be administered in patients receiving ketoconazole, itraconazole, ritonavir, indinavir, clarithromycin, or other strong CYP3A4 inhibitors. Conivaptan increases levels of simvastatin, digoxin, amlodipine, and midazolam. The most common adverse effect of conivaptan is an infusion site reaction. Other adverse effects include headache, hypertension, hypotension, hypokalemia, and pyrexia.