Late Distal Tubule And Collecting Duct

60 mV 75 mV

Channel Saccharomyces
FIGURE 28-5 NaCl reabsorption in distal convoluted tubule and mechanism of diuretic action of Na+—Cl" sym-port inhibitors. CA, carbonic anhydrase; S, symporter; CH, ion channel. Numbers in parentheses indicate stoichiometry. BL and LM indicate basolateral and luminal membranes, respectively.

Amiloride and triamterene block epithelial Na+ channels in the luminal membrane of principal cells in the late distal tubule and collecting duct, perhaps by competing with Na+ for negatively charged areas within the pore of the Na+ channel. The amiloride-sensitive Na+ channel (called ENaC) consists of three subunits (a, b, and g). Although the a subunit is sufficient for channel activity, maximal Na+ permeability is induced when all three subunits are coexpressed in the same cell. Liddle's syndrome (pseudohyperaldosteronism) is an autosomal dominant form of low-renin, volume-expanded hypertension that is due to mutations in the b or g subunits, leading to increased basal activity of ENaC. Amiloride is very effective in treating hypertension in patients carrying these mutations.

EFFECTS ON URINARY EXCRETION Since the late distal tubule and collecting duct have limited capacity to reabsorb solutes, blockade of Na+ channels in this part of the nephron only mildly increases the excretion rates of Na+ and Cl- (-2% of filtered load). Blockade of Na+ channels hyperpolarizes the luminal membrane, reducing the lumen-negative transepithelial voltage. Since the lumen-negative potential difference normally opposes cation reabsorption and facilitates cation secretion, attenuation of the lumen-negative voltage decreases the excretion rates of K+, H+, Ca2+, and Mg2+. 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 The relative potency, oral bioavailability, plasma t1/2, and route of elimination for amiloride and triamterene are listed in Table 28-6. Amiloride is eliminated predominantly by urinary excretion of intact drug. Triamterene is metabolized extensively to an active metabolite, 4-hydroxytriamterene sulfate, and this metabolite is excreted in the urine. Therefore, the toxicity of triamterene may be enhanced in both hepatic disease (decreased metabolism of triamterene) and renal failure (decreased urinary excretion of active metabolite).


The most dangerous adverse effect of 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. Pentamidine and high-dose trimethoprim are used often to treat Pneumocystis carinii pneumonia in patients with acquired immune deficiency syndrome (AIDS). Because these compounds weakly inhibit ENaC, they too may cause

Table 28-6

Inhibitors of Renal Epithelial Na+ Channels (K+-Sparing Diuretics)

Drug Relative Oral t1/2 Route of

(trade name) Structure Potency Availability (hours) Elimination

Drug Relative Oral t1/2 Route of

(trade name) Structure Potency Availability (hours) Elimination

Mosty Mapa
abbreviations: R, renal excretion of intact drug; M, metabolism; however, triamterene is transformed into an active metabolite that is excreted in the urine.

hyperkalemia, which may explain the frequent occurrence of hyperkalemia in AIDS patients. 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 the treatment of edema or hypertension. Rather, 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; consequently, the combination of a Na+-channel inhibitor with a thi-azide or loop diuretic tends to result in normal values of plasma K+. Liddle's syndrome can be treated effectively with Na+-channel inhibitors. Approximately 5% of people of African origin carry a T594M polymorphism in the b subunit of ENaC, and amiloride is particularly effective in lowering blood pressure in hypertensive patients who carry this polymorphism. Aerosolized amiloride improves 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 the cells of the collecting tubules.


Mineralocorticoids cause salt and water retention and increase the excretion of K+ and H+ by binding to specific mineralocorticoid receptors (MRs). Currently, two MR antagonists are available in the U.S., spironolactone and eplerenone; two others are available elsewhere (Table 28-7). Epithelial cells in the late distal tubule and collecting duct contain cytosolic MRs that have a high affinity for aldosterone. Aldosterone enters the epithelial cell from the basolateral membrane and binds to MRs; the MR-aldosterone complex translocates to the nucleus, where it regulates the expression of multiple gene products called aldosterone-inducedproteins (AlPs). Figure 28-6 illustrates some of the proposed effects of AlPs. The net effect of AlPs is to increase Na+ conductance of the lumi-nal membrane and sodium pump activity of the basolateral membrane. Consequently, transepithe-lial NaCl transport is enhanced, and the lumen-negative transepithelial voltage is increased. The latter effect increases the driving force for secretion of K+ and H+ into the tubular lumen.

Spironolactone and eplerenone competitively inhibit the binding of aldosterone to the MR. Unlike the MR-aldosterone complex, the MR-spironolactone complex is unable to induce the synthesis of AlPs. Since spironolactone and eplerenone block the 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 that of the Na+-channel inhibitors, the clinical efficacy of MR antagonists is a function of endogenous levels of aldosterone. The higher the levels of endogenous aldosterone, the greater are 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 the 9,11-epoxide group, eplerenone has very low affinity for progesterone and androgen receptors (<1% and <0.1%, respectively) compared with spironolactone. Therapeutic concentrations of spironolactone block human ether-a-go-go-related gene (HERG) K+ channels, and this may account for the antiarrythmic effects of spironolactone in heart failure. High concentrations of spironolactone can interfere with steroid biosynthesis by inhibiting CYPs (see Chapter 59).

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 hours). However, an active metabolite of spironolactone, canrenone, has a t1/2 of -16.5 hours, which prolongs the biological effects of spironolactone. Although not available in the U.S., canrenone and canrenoate also are in clinical use. Canrenoate is not active per se but is converted to canrenone in the body. Eplerenone has good oral availability and is eliminated with a t1/2 of -5 hours, primarily by conversion to inactive metabolites by hepatic CYP3A4.

Table 28-7

Mineralocorticoid Receptor Antagonists (Aldosterone Antagonists, K+-Sparing Diuretics)


(trade name)


Oral t1/2 Route of

Availability (hours) Elimination




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