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 ⁺ .

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.

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.

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−’>HC?3−HCO3−
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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−’>HC?3−HCO3−
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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.

In the Clinic

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