Physiology of Diuretic Action





Objectives


Upon completion of this chapter, the student should be able to answer the following questions:




  • What effects do diuretics have on Na + handling by the kidneys?



  • What effects do aquaretics have on water handling by the kidneys?



  • Why do diuretics decrease the volume of the extracellular fluid?



  • What mechanisms are involved in delivering diuretics to their sites of action along the nephron?



  • What is the primary nephron site where each class of diuretics acts, and what is the specific membrane transport protein affected?



  • How do nephrons alter their function in response to diuretics, and how does this affect the action of diuretics?



  • What are the effects of the various classes of diuretics on the renal handling of K + , Ca ++ , bicarbonate ( <SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−’>HC𝑂3HCO3
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    HC O 3 −
    ), inorganic phosphate (P i ), and solute-free water?





Key Terms


Diuretics


Natriuresis


Aquaretics


Water diuresis


Diuretic braking phenomenon


Steady state


Osmotic diuretics


Carbonic anhydrase inhibitors


Loop diuretics


Organic anion secretory system


Thiazide diuretics


K + -sparing diuretics


Organic cation secretory system


Syndrome of inappropriate antidiuresis (SIAD)


Syndrome of inappropriate antidiuretic hormone (SIADH)


Diuretics , as the name implies, are drugs that cause an increase in urine output. It is important, however, to distinguish this diuresis from that which occurs after the ingestion of large volumes of water. In the latter case the urine is primarily made up of water, and solute excretion is not increased. In contrast, diuretics result in the enhanced excretion of both solute and water.


All diuretics (with the exception of aquaretics, which will be discussed) have as their common mode of action the primary inhibition of Na + reabsorption by the nephron. Consequently, they cause an increase in the excretion of Na + , termed natriuresis . However, the effects of diuretics are not limited to Na + handling. The renal handling of many other solutes also is influenced, usually as a consequence of alterations in Na + transport. Drugs have been developed that block the action of arginine vasopressin (AVP) on the distal tubule and collecting duct. These drugs, called aquaretics , cause a water diuresis . This chapter reviews the cellular mechanisms of action of various diuretics and the nephron sites at which these diuretics act. In addition to their effects on Na + handling by the nephron, their effects on the renal handling of other solutes (e.g., K + , Ca ++ , inorganic phosphate [P i ], and bicarbonate [ <SPAN role=presentation tabIndex=0 id=MathJax-Element-2-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−’>HC𝑂3HCO3
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]) and of water are considered. The effects of aquaretics on water excretion also are discussed.




General Principles of Diuretic Action


The primary action of diuretics is to increase the excretion of Na + . As described in Chapter 6 , alterations in Na + excretion by the kidneys result in alterations in the volume of the extracellular fluid (ECF) compartment. Consequently, diuretics decrease the volume of the ECF. Indeed, diuretics commonly are given in clinical situations when the ECF compartment is expanded, with the intent of reducing its volume. Because the ECF volume also determines blood volume and pressure, diuretics commonly are used in the therapy of hypertension.


Although generally predictable for a particular class of diuretics, the effects of diuretic administration can be quite variable. Several factors are important in determining the overall effect of a particular diuretic:



  • 1.

    The nephron segment where the diuretic acts


  • 2.

    The response of nephron segments not directly affected by the diuretic


  • 3.

    The delivery of sufficient quantities of the diuretic to its site of action


  • 4.

    The volume of the ECF



Sites of Action of Diuretics


Fig. 10.1 depicts the nephron sites at which the different classes of diuretics act. The osmotic diuretics act along the proximal tubule and portions of the thin descending limb of Henle’s loop (i.e., those portions of the nephron that have a high water permeability). The carbonic anhydrase inhibitors act primarily in the proximal tubule. The thick ascending limb of Henle’s loop is the site of action of the loop diuretics. The early portion of the distal tubule is the site of action of the thiazide diuretics, and the K + -sparing diuretics act primarily on the late portion of the distal tubule and the cortical portion of the collecting duct (i.e., the aldosterone-sensitive distal nephron [ASDN]) where they inhibit not only Na + reabsorption but also K + secretion. The K + -sparing diuretics also can inhibit Na + reabsorption in portions of the collecting duct that do not secrete K + .




Fig. 10.1


Sites of action of diuretics and aquaretics along the nephron. CCD, Cortical collecting duct; DT, distal tubule; PT, proximal tubule; TAL, thick ascending limb.


The site of action of a diuretic in turn determines the magnitude of the associated natriuresis ( Table 10.1 ). For example, diuretics acting on the thick ascending limb of Henle’s loop cause a larger diuresis than diuretics acting on the early portion of the distal tubule, because a larger portion of the filtered Na + is reabsorbed by the thick ascending limb (see Chapter 4, Chapter 6 ). The effect diuretics have on the handling of solutes other than Na + also depends on the site of action. Examples illustrating this point are given in subsequent sections.



TABLE 10.1

Diuretic Effects on Renal Excretion




























































Diuretic Na + Excretion K + Excretion <SPAN role=presentation tabIndex=0 id=MathJax-Element-3-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−’>HC𝑂3HCO3
HCO3−
HCO3
HC O 3 −
Excretion
Ca ++ Excretion Free Water Excretion Free Water Reabsorption
Osmotic diuretic 10%
CAI 5%–10%
Loop diuretic 25%
Thiazide diuretic 5%–10% NC
K + -sparing diuretic 3%–5% NC NC NC
Aquaretics 0% NC NC NC

CAI, Carbonic anhydrase inhibitor; NC, no change.

All the effects (except <SPAN role=presentation tabIndex=0 id=MathJax-Element-4-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−’>HC𝑂3HCO3
HCO3−
HCO3
HC O 3 −
excretion) reflect the initial effect of the diuretic. The effects of loop and thiazide diuretics on <SPAN role=presentation tabIndex=0 id=MathJax-Element-5-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−’>HCO3HCO3
HCO3−
HCO3
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excretion occur with prolonged use of these drugs and are secondary to the diuretic-induced decrease in extracellular fluid volume.

Percentage of filtered Na + excreted into the urine



Response of Other Nephron Segments


When a diuretic inhibits Na + reabsorption at one nephron site, it causes increased delivery of Na + and water to more distal segments. The function of these more distal segments and their ability or inability to handle this increased load ultimately determine the overall effect of the diuretic on urinary solute and water excretion. Examples of this phenomenon are considered in detail with discussion of each of the various diuretics. In addition, diuretic-induced changes in ECF volume (discussed later in this chapter) may modulate Na + transport in segments of the nephron not directly affected by the diuretic and thereby influence the degree of natriuresis.


Adequate Delivery of Diuretics to Their Site of Action


The effect of a diuretic on Na + excretion also depends on the delivery of adequate quantities of the drug to its site of action. With the exception of the aldosterone antagonists, which act intracellularly, diuretics act from the lumen of the nephron (carbonic anhydrase inhibitors have both luminal and intracellular sites of action). Diuretics gain access to the lumen by glomerular filtration and through secretion by the organic anion and organic cation secretory systems located in the proximal tubule (see Chapter 4 ). Because some diuretics are bound to plasma proteins (e.g., loop diuretics), their secretion by the proximal tubule is the primary mechanism for delivery of the diuretic to its site of action in the lumen of the nephron. Thus the effect of a diuretic can be blunted if, for example, it is administered with another drug that competes for the same organic anion and organic cation secretory mechanism.


Volume of the Extracellular Fluid


The effect of a diuretic also depends on the volume of the ECF. As described in Chapter 6 , when the volume of the ECF is decreased, the glomerular filtration rate (GFR) is reduced, thereby reducing the amount of filtered Na + . In addition, Na + reabsorption by the nephron is enhanced. Thus the effect of a diuretic that acts on the distal tubule would be blunted if administered in the setting of a reduced ECF volume. Under this condition, the decreased GFR (i.e., decreased filtered Na + ), together with enhanced Na + reabsorption by the proximal tubule, would result in the delivery of a smaller quantity of Na + to the distal tubule. Thus even if the diuretic completely inhibited Na + reabsorption in the distal tubule, the associated natriuresis would be less than would occur if the ECF volume were normal.




Sites of Action of Diuretics


Fig. 10.1 depicts the nephron sites at which the different classes of diuretics act. The osmotic diuretics act along the proximal tubule and portions of the thin descending limb of Henle’s loop (i.e., those portions of the nephron that have a high water permeability). The carbonic anhydrase inhibitors act primarily in the proximal tubule. The thick ascending limb of Henle’s loop is the site of action of the loop diuretics. The early portion of the distal tubule is the site of action of the thiazide diuretics, and the K + -sparing diuretics act primarily on the late portion of the distal tubule and the cortical portion of the collecting duct (i.e., the aldosterone-sensitive distal nephron [ASDN]) where they inhibit not only Na + reabsorption but also K + secretion. The K + -sparing diuretics also can inhibit Na + reabsorption in portions of the collecting duct that do not secrete K + .




Fig. 10.1


Sites of action of diuretics and aquaretics along the nephron. CCD, Cortical collecting duct; DT, distal tubule; PT, proximal tubule; TAL, thick ascending limb.


The site of action of a diuretic in turn determines the magnitude of the associated natriuresis ( Table 10.1 ). For example, diuretics acting on the thick ascending limb of Henle’s loop cause a larger diuresis than diuretics acting on the early portion of the distal tubule, because a larger portion of the filtered Na + is reabsorbed by the thick ascending limb (see Chapter 4, Chapter 6 ). The effect diuretics have on the handling of solutes other than Na + also depends on the site of action. Examples illustrating this point are given in subsequent sections.



TABLE 10.1

Diuretic Effects on Renal Excretion




























































Diuretic Na + Excretion K + Excretion <SPAN role=presentation tabIndex=0 id=MathJax-Element-6-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−’>HC𝑂3HCO3
HCO3−
HCO3
HC O 3 −
Excretion
Ca ++ Excretion Free Water Excretion Free Water Reabsorption
Osmotic diuretic 10%
CAI 5%–10%
Loop diuretic 25%
Thiazide diuretic 5%–10% NC
K + -sparing diuretic 3%–5% NC NC NC
Aquaretics 0% NC NC NC

CAI, Carbonic anhydrase inhibitor; NC, no change.

All the effects (except <SPAN role=presentation tabIndex=0 id=MathJax-Element-7-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−’>HC𝑂3HCO3
HCO3−
HCO3
HC O 3 −
excretion) reflect the initial effect of the diuretic. The effects of loop and thiazide diuretics on <SPAN role=presentation tabIndex=0 id=MathJax-Element-8-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−’>HCO3HCO3
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excretion occur with prolonged use of these drugs and are secondary to the diuretic-induced decrease in extracellular fluid volume.

Percentage of filtered Na + excreted into the urine





Response of Other Nephron Segments


When a diuretic inhibits Na + reabsorption at one nephron site, it causes increased delivery of Na + and water to more distal segments. The function of these more distal segments and their ability or inability to handle this increased load ultimately determine the overall effect of the diuretic on urinary solute and water excretion. Examples of this phenomenon are considered in detail with discussion of each of the various diuretics. In addition, diuretic-induced changes in ECF volume (discussed later in this chapter) may modulate Na + transport in segments of the nephron not directly affected by the diuretic and thereby influence the degree of natriuresis.




Adequate Delivery of Diuretics to Their Site of Action


The effect of a diuretic on Na + excretion also depends on the delivery of adequate quantities of the drug to its site of action. With the exception of the aldosterone antagonists, which act intracellularly, diuretics act from the lumen of the nephron (carbonic anhydrase inhibitors have both luminal and intracellular sites of action). Diuretics gain access to the lumen by glomerular filtration and through secretion by the organic anion and organic cation secretory systems located in the proximal tubule (see Chapter 4 ). Because some diuretics are bound to plasma proteins (e.g., loop diuretics), their secretion by the proximal tubule is the primary mechanism for delivery of the diuretic to its site of action in the lumen of the nephron. Thus the effect of a diuretic can be blunted if, for example, it is administered with another drug that competes for the same organic anion and organic cation secretory mechanism.




Volume of the Extracellular Fluid


The effect of a diuretic also depends on the volume of the ECF. As described in Chapter 6 , when the volume of the ECF is decreased, the glomerular filtration rate (GFR) is reduced, thereby reducing the amount of filtered Na + . In addition, Na + reabsorption by the nephron is enhanced. Thus the effect of a diuretic that acts on the distal tubule would be blunted if administered in the setting of a reduced ECF volume. Under this condition, the decreased GFR (i.e., decreased filtered Na + ), together with enhanced Na + reabsorption by the proximal tubule, would result in the delivery of a smaller quantity of Na + to the distal tubule. Thus even if the diuretic completely inhibited Na + reabsorption in the distal tubule, the associated natriuresis would be less than would occur if the ECF volume were normal.




Diuretic Braking Phenomenon


As illustrated in Fig. 10.2 , administration of a diuretic to a person with fixed Na + intake results in a short-lived natriuresis. The transient response, called the diuretic braking phenomenon , reflects several changes in renal function that are both a direct effect of the diuretic and secondary to changes in the volume of the ECF. One component of this response is that diuretic-induced inhibition of Na + reabsorption in the targeted nephron segment increases Na + delivery to more distal nephron segments and simulates Na + reabsorption at these sites. A second important component of this response is that loss of sodium chloride (NaCl) and water from the body as a result of diuretic action decreases the volume of the ECF. This decrease in turn is sensed by the body’s vascular baroreceptors and effector mechanisms, prompting them to increase NaCl and water conservation by the kidneys (see Chapter 6 for details).



At the Cellular Level


Studies in experimental animals have found that loop and thiazide diuretics increase the expression of the transporters they inhibit. For example, loop diuretics, which inhibit the Na + -K + -2Cl cotransporter (NKCC2) in the apical membrane of the cells of the thick ascending limb of Henle’s loop, also increase the expression of the transporter in this segment. Similarly, thiazide diuretics, which inhibit the Na + -Cl symporter (NCC) in the apical membrane of the early portion of the distal tubule, also increase the expression of these transporters in this segment. In addition, both loop and thiazide diuretics increase the expression of the Na + channel (epithelial sodium channel [ENaC]) in the late portion of the distal tubule and collecting duct. Thiazide diuretics also increase the expression of aquaporin-2 in the principal cells of the late portion of the distal tubule and the collecting duct. Whether this effect is direct or indirect (i.e., related to changes in ECF volume) is uncertain. Regardless of the mechanism, the increased expression of aquaporin-2 is expected to increase water reabsorption by the arginine vasopressin (AVP)–sensitive nephron segments.


With the diuretic-induced decrease in the ECF volume, the renin-angiotensin-aldosterone system is activated, renal sympathetic nerve activity is increased, and AVP secretion is stimulated, which in combination act to reduce urinary NaCl and water excretion (see Chapter 5, Chapter 6 for details). At the cellular level, angiotensin II increases the expression of the Na + -Cl symporter in the early portion of the distal tubule, and aldosterone increases the expression of ENaC in the late distal tubule and collecting duct. AVP also increases the expression of NKCC2 in the thick ascending limb of Henle’s loop, NCC in the early portion of the distal tubule, and ENaC in the late distal tubule and collecting duct. Finally, angiotensin II increases the abundance of the Na + -H + antiporter (NHE3) in the proximal tubule. Upregulation of these transporters by diuretics reduces their efficacy and, when the diuretic administration is terminated, results in a rapid increase in NaCl reabsorption.




Fig. 10.2


Effect of long-term diuretic therapy on renal Na + excretion. Because diuretics induce a natriuresis, extracellular fluid volume is reduced, which is detected as a decrease in body weight.


As a result of the braking phenomenon, a new steady state is reached where even with continued administration of the diuretic, urinary Na + excretion once again equals intake. However, this steady state occurs at a reduced ECF volume, which is detected as a decrease in body weight. When diuretic therapy is discontinued, renal Na + excretion is reduced. After a period of positive Na + balance, during which the ECF returns to normal (i.e., return of body weight to its original value), a new steady state is again achieved.


The concept of steady state deserves special emphasis. Normally, persons are in steady-state balance with regard to solute (e.g., Na + ) and water, with intake equaling excretion. Administration of a diuretic temporarily disrupts this balance by increasing solute and water excretion, and a negative balance exists. However, solute and water excretion cannot exceed intake indefinitely, and a new steady state eventually is achieved. In this new steady state, intake and excretion are again balanced, but the ECF volume is reduced as a result of diuretic-induced excretion of NaCl and water. In general, when a person has been taking a diuretic for several days or longer, a new steady state is achieved. If Na + intake is not increased, the ECF volume is decreased in proportion to the degree of negative Na + balance.





At the Cellular Level


Studies in experimental animals have found that loop and thiazide diuretics increase the expression of the transporters they inhibit. For example, loop diuretics, which inhibit the Na + -K + -2Cl cotransporter (NKCC2) in the apical membrane of the cells of the thick ascending limb of Henle’s loop, also increase the expression of the transporter in this segment. Similarly, thiazide diuretics, which inhibit the Na + -Cl symporter (NCC) in the apical membrane of the early portion of the distal tubule, also increase the expression of these transporters in this segment. In addition, both loop and thiazide diuretics increase the expression of the Na + channel (epithelial sodium channel [ENaC]) in the late portion of the distal tubule and collecting duct. Thiazide diuretics also increase the expression of aquaporin-2 in the principal cells of the late portion of the distal tubule and the collecting duct. Whether this effect is direct or indirect (i.e., related to changes in ECF volume) is uncertain. Regardless of the mechanism, the increased expression of aquaporin-2 is expected to increase water reabsorption by the arginine vasopressin (AVP)–sensitive nephron segments.


With the diuretic-induced decrease in the ECF volume, the renin-angiotensin-aldosterone system is activated, renal sympathetic nerve activity is increased, and AVP secretion is stimulated, which in combination act to reduce urinary NaCl and water excretion (see Chapter 5, Chapter 6 for details). At the cellular level, angiotensin II increases the expression of the Na + -Cl symporter in the early portion of the distal tubule, and aldosterone increases the expression of ENaC in the late distal tubule and collecting duct. AVP also increases the expression of NKCC2 in the thick ascending limb of Henle’s loop, NCC in the early portion of the distal tubule, and ENaC in the late distal tubule and collecting duct. Finally, angiotensin II increases the abundance of the Na + -H + antiporter (NHE3) in the proximal tubule. Upregulation of these transporters by diuretics reduces their efficacy and, when the diuretic administration is terminated, results in a rapid increase in NaCl reabsorption.




Mechanisms of Action of Diuretics


Osmotic Diuretics


Osmotic diuretics , as the name implies, are agents that inhibit the reabsorption of solute and water by altering osmotic driving forces along the nephron. Unlike the other classes of diuretics, osmotic diuretics do not inhibit a specific membrane transport protein; they simply affect water transport across the cells of the nephron through the generation of an osmotic pressure gradient. The best example of an exogenous osmotic diuretic is the sugar mannitol. When present in abnormally high concentrations, freely filtered endogenous substances such as glucose (e.g., in patients with diabetes mellitus) and urea (e.g., in patients with renal disease whose plasma urea levels are elevated) also can act as osmotic diuretics. a


Osmotic diuretics (e.g., mannitol) gain access to the proximal tubular fluid by glomerular filtration. Because they are not reabsorbed or are only poorly reabsorbed, they remain within the tubular lumen, where they can exert an osmotic pressure that inhibits tubular fluid reabsorption. Osmotic diuretics affect fluid reabsorption in the segments that have high permeability to water (i.e., the proximal tubule and portions of the thin descending limb of Henle’s loop). Because of the large volumes of filtrate reabsorbed in the proximal tubule (60% to 70% of the filtrate), this nephron site is most important when considering the action of osmotic diuretics.


As described in Chapter 4 , reabsorption of tubular fluid by the proximal tubule is essentially an isosmotic process (i.e., the osmolality of the reabsorbed fluid is only slightly hyperosmotic compared with that of tubular fluid). Solute (primarily NaCl) is actively reabsorbed by the proximal tubule cells. This reabsorption sets up a small osmotic pressure difference across the tubule, with the tubular fluid being 3 to 5 mOsm/kg H 2 O hypoosmotic with respect to the interstitial fluid. Given the fact that water is readily able to cross the proximal tubule, this small osmotic pressure gradient is sufficient to cause water reabsorption. Also, as water flows from the lumen to the interstitium, it brings additional solute with it by solvent drag.


When an osmotic diuretic is present in the tubular fluid, its concentration increases progressively as a result of NaCl and water reabsorption by the nephron. With this increase in concentration, an osmotic gradient develops opposite to the normal gradient generated by NaCl reabsorption. As a result, both NaCl (solvent drag component) and water reabsorption are reduced. With an osmotic diuresis, an increase in blood flow to the medulla of the kidney also occurs. This increase in blood flow dissipates the standing interstitial osmotic gradient (see Chapter 5 ) and thus also impairs water reabsorption by the descending limb of Henle’s loop and the medullary collecting duct.


Some of the Na + that is not reabsorbed by the proximal tubule is reabsorbed downstream by the thick ascending limb, distal tubule, and collecting duct. Thus the degree of natriuresis seen with osmotic diuretics is less than expected on the basis of the magnitude of proximal tubule reabsorption. Although Na + excretion rates as high as 60% of the filtered Na + have been reported in experimental situations, the usual natriuresis seen in persons treated with osmotic diuretics is only about 10% of the filtered Na + .


Carbonic Anhydrase Inhibitors


Carbonic anhydrase inhibitors (e.g., acetazolamide) reduce Na + reabsorption by their effect on carbonic anhydrase. This enzyme is abundant in the proximal tubule and therefore represents the major site of action of these diuretics. Carbonic anhydrase also is present in other cells along the nephron (e.g., thick ascending limb of Henle’s loop and intercalated cells of the collecting duct), and administration of carbonic anhydrase inhibitors affects the activity of the enzyme at these sites as well. However, the effects of these diuretics are almost entirely attributed to their inhibition of the enzyme in the proximal tubule. This phenomenon reflects the fact that approximately one-third of proximal tubule Na + reabsorption occurs in exchange for H + (through the Na + -H + antiporter) and thus depends on the activity of carbonic anhydrase (see Chapter 8 ).


Even though one-third of proximal tubule Na + reabsorption is coupled to the secretion of H + , inhibition of this process by the carbonic anhydrase inhibitors does not result in a large natriuresis for several reasons. First, even with complete inhibition of carbonic anhydrase, some Na + reabsorption (linked to bicarbonate reabsorption) still occurs. Second, downstream nephron segments increase their reabsorption of Na + (e.g., the thick ascending limb, distal tubule, and collecting duct). Third, increased delivery of Na + to the macula densa leads to a reduction in the GFR by the tubuloglomerular feedback mechanism. Finally, with long-term administration, a metabolic acidosis develops, which further decreases the effect of carbonic anhydrase inhibitors by reducing the filtration of <SPAN role=presentation tabIndex=0 id=MathJax-Element-9-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−’>HC𝑂3HCO3
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(i.e., the percentage of Na + reabsorbed with <SPAN role=presentation tabIndex=0 id=MathJax-Element-10-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−’>HC𝑂3HCO3
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in the proximal tubule is reduced). Typically administration of carbonic anhydrase inhibitors results in Na + excretion rates that are 5% to 10% of the filtered Na + .


Loop Diuretics


Loop diuretics (e.g., furosemide, bumetanide, torsemide, and ethacrynic acid) are organic anions that enter the tubular lumen primarily through secretion by the organic anion secretory system of the proximal tubule (see Chapter 4 ). They directly inhibit Na + reabsorption by the thick ascending limb of Henle’s loop by blocking the Na + -K + -2Cl symporter located in the apical membrane of these cells (see Chapter 4 ). By this action they not only inhibit Na + reabsorption but also disrupt the ability of the kidneys to dilute and concentrate the urine. Dilution is impaired because solute (NaCl) reabsorption by the water-impermeable thick ascending limb of Henle’s loop is inhibited. NaCl reabsorption by the medullary portion of the thick ascending limb also is critical for the generation and maintenance of an elevated medullary interstitial fluid osmolality. Therefore inhibition of NaCl transport by loop diuretics results in a decrease in the osmolality of the medullary interstitial fluid. With a decrease in medullary interstitial fluid osmolality, water reabsorption from the collecting duct is impaired and the concentrating ability of the kidneys is reduced. Water reabsorption from some portions of the thin descending limb of Henle’s loop also is impaired by loop diuretics, again because of the decrease in medullary interstitial fluid osmolality. This decrease in thin descending limb water reabsorption in part accounts for the increase in water excretion seen with loop diuretics.


Loop diuretics are the most potent diuretics available, increasing the excretion of Na + to as much as 25% of the amount filtered. This large natriuresis reflects the fact that the thick ascending limb normally reabsorbs approximately 20% to 25% of the filtered Na + and that downstream segments of the nephron have a limited ability to reabsorb the excess Na + delivered as a consequence of loop diuretic action. However, with long-term administration of loop diuretics there is hypertrophy of cells in the distal tubule, which is associated with enhanced Na + reabsorption. As a result, the natriuresis associated with long-term loop diuretic usage is blunted from that which is seen acutely.


Thiazide Diuretics


Like the loop diuretics, thiazide diuretics (e.g., hydrochlorothiazide, chlorthalidone, and metolazone) b are organic anions. Because they largely are bound to plasma proteins, they gain access to the tubular lumen primarily by secretion in the proximal tubule. They inhibit Na + reabsorption in the early portion of the distal tubule by blocking the Na + -Cl symporter in the apical membrane of these cells (see Chapter 4 ). Because water cannot cross this portion of the nephron, it is a site where the urine is diluted. Therefore thiazides reduce the ability to dilute the urine maximally by inhibiting NaCl reabsorption. Because thiazide diuretics act in the cortex and not the medulla, they do not affect the ability of the kidneys to concentrate the urine maximally. Natriuresis with thiazide diuretics is 5% to 10% of the filtered Na + . As noted previously (see Chapter 8 ), thiazide diuretics also inhibit a component of NaCl reabsorption carried out by the B- or β-intercalated cell. To what degree this action contributes to the overall natriuresis seen with thiazide diuretics is unclear.


K + -Sparing Diuretics


K + -sparing diuretics act on the region of the nephron where K + secretion occurs (i.e., the late portion of the distal tubule and cortical collecting duct [ASDN]). They produce a small natriuresis (3% to 5% of the filtered Na + ), reflecting the amount of Na + reabsorbed by this region of the nephron. As the name implies, their utility lies in their ability to inhibit K + secretion by this region of the nephron.


There are two classes of K + -sparing diuretics: one acts by antagonizing the action of aldosterone on principal cells (e.g., spironolactone and eplerenone), whereas the other class (e.g., amiloride and triamterene) inhibits the Na + -selective channel ENaC in the apical membrane of principal cells. Amiloride and triamterene are organic cations that enter the tubular lumen primarily by secretion by the organic cation secretory system of the proximal tubule (see Chapter 4 ).


As described in detail in Chapter 6, Chapter 7 , aldosterone stimulates both Na + reabsorption and K + secretion by principal cells of the late distal tubule and collecting duct. Thus in the presence of an aldosterone antagonist, these effects are inhibited and both Na + reabsorption and K + secretion are reduced.


The ability of the Na + channel blockers amiloride and triamterene to inhibit Na + reabsorption and K + secretion is similar to that of spironolactone, but the cellular mechanism is different. Amiloride and triamterene block the entry of Na + into the principal cell by directly inhibiting ENaC in the apical membrane. With decreased Na + entry into the cell, reduced Na + extrusion occurs across the basolateral membrane through Na + -K + –adenosine triphosphatase (ATPase). This effect in turn reduces cellular K + uptake and ultimately its secretion into the tubular fluid. Inhibition of apical membrane Na + channels also alters the electrical profile across the luminal membrane, with the voltage across this membrane increasing in magnitude. Because of this voltage change, the electrochemical gradient for K + movement out of the cell into the tubule lumen is reduced. This membrane voltage effect also contributes to the inhibition of K + secretion.


Oct 10, 2019 | Posted by in NEPHROLOGY | Comments Off on Physiology of Diuretic Action
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