CARBONIC ANHYDRASE INHIBITORS
Carbonic anhydrase is present in many nephron sites, but the predominant location of this enzyme is the epithelial cells of the PCT (Figure 15–2), where it catalyzes the dehydration of H2CO3 to CO2 at the luminal membrane and rehydration of CO2 to H2CO3 in the cytoplasm as previously described. By blocking carbonic anhydrase, inhibitors blunt NaHCO3 reabsorption and cause diuresis.
Carbonic anhydrase inhibitors were the forerunners of modern diuretics. They were discovered in 1937 when it was found that bacteriostatic sulfonamides caused an alkaline diuresis and hyperchloremic metabolic acidosis. With the development of newer agents, carbonic anhydrase inhibitors are now rarely used as diuretics, but they still have several specific applications that are discussed below. The prototypical carbonic anhydrase inhibitor is acetazolamide.
The carbonic anhydrase inhibitors are well absorbed after oral administration. An increase in urine pH from the HCO3− diuresis is apparent within 30 minutes, is maximal at 2 hours, and persists for 12 hours after a single dose. Excretion of the drug is by secretion in the proximal tubule S2 segment. Therefore, dosing must be reduced in renal insufficiency.
Inhibition of carbonic anhydrase activity profoundly depresses HCO3− reabsorption in the PCT. At maximal safe inhibitor dosage, 85% of the HCO3− reabsorptive capacity of the superficial PCT is inhibited. Some HCO3− can still be absorbed at other nephron sites by carbonic anhydrase–independent mechanisms, so the overall effect of maximal acetazolamide dosage is only about 45% inhibition of whole kidney HCO3− reabsorption. Nevertheless, carbonic anhydrase inhibition causes significant HCO3− losses and hyperchloremic metabolic acidosis (Table 15–2). Because of reduced HCO3− in the glomerular filtrate and the fact that HCO3− depletion leads to enhanced NaCl reabsorption by the remainder of the nephron, the diuretic efficacy of acetazolamide decreases significantly with use over several days.
TABLE 15–2Changes in urinary electrolyte patterns and body pH in response to diuretic drugs. ||Download (.pdf) TABLE 15–2 Changes in urinary electrolyte patterns and body pH in response to diuretic drugs.
|Group ||Urinary Electrolytes ||Body pH |
|NaCl ||NaHCO3 ||K+ |
|Carbonic anhydrase inhibitors ||+ ||+++ ||+ ||↓ |
|Loop agents ||++++ ||0 ||+ ||↑ |
|Thiazides ||++ ||+ ||+ ||↑ |
|Loop agents plus thiazides ||+++++ ||+ ||++ ||↑ |
|K+-sparing agents ||+ ||(+) ||− ||↓ |
At present, the major clinical applications of acetazolamide involve carbonic anhydrase–dependent HCO3− and fluid transport at sites other than the kidney. The ciliary body of the eye secretes HCO3− from the blood into the aqueous humor. Likewise, formation of cerebrospinal fluid (CSF) by the choroid plexus involves HCO3− secretion. Although these processes remove HCO3− from the blood (the direction opposite of that in the proximal tubule), they are similarly inhibited by carbonic anhydrase inhibitors.
Clinical Indications & Dosage
The reduction of aqueous humor formation by carbonic anhydrase inhibitors decreases the intraocular pressure (Table 15–3). This effect is valuable in the management of glaucoma in some patients, making it the most common indication for use of carbonic anhydrase inhibitors (see Table 10–3). Topically active agents, which reduce intraocular pressure without producing renal or systemic effects, are available (dorzolamide, brinzolamide).
TABLE 15–3Carbonic anhydrase inhibitors used orally in the treatment of glaucoma. ||Download (.pdf) TABLE 15–3 Carbonic anhydrase inhibitors used orally in the treatment of glaucoma.
B. Urinary Alkalinization
Uric acid and cystine are relatively insoluble and may form stones in acidic urine. Therefore, in cystinuria, a disorder of cystine reabsorption, solubility of cystine can be enhanced by increasing urinary pH to 7–7.5 with carbonic anhydrase inhibitors. In the case of uric acid, pH needs to be raised only to 6–6.5. In the absence of HCO3− administration, these effects of acetazolamide last only 2–3 days, so prolonged therapy requires oral HCO3−. As a result, these agents have proved to be of limited utility for this indication.
Metabolic alkalosis is generally treated by correction of abnormalities in total body K+, intravascular volume, or mineralocorticoid levels. However, when the alkalosis is due to excessive use of diuretics in patients with severe heart failure, replacement of intravascular volume may be contraindicated. In these cases, acetazolamide can be useful in correcting the alkalosis as well as producing a small additional diuresis for correction of volume overload. Acetazolamide can also be used to rapidly correct the metabolic alkalosis that may appear following the correction of respiratory acidosis.
D. Acute Mountain Sickness
Weakness, dizziness, insomnia, headache, and nausea can occur in mountain travelers who rapidly ascend above 3000 m. The symptoms are usually mild and last for a few days. In more serious cases, rapidly progressing pulmonary or cerebral edema can be life-threatening. By decreasing CSF formation and by decreasing the pH of the CSF and brain, acetazolamide can increase ventilation and diminish symptoms of mountain sickness. This mild metabolic central and CSF acidosis is also useful in the treatment of sleep apnea.
Carbonic anhydrase inhibitors have been used as adjuvants in the treatment of epilepsy and in some forms of hypokalemic periodic paralysis. They are also useful in treating patients with CSF leakage (usually caused by tumor or head trauma, but often idiopathic). By reducing the rate of CSF formation and intracranial pressure, carbonic anhydrase inhibitors can significantly slow the rate of CSF leakage. They also increase urinary phosphate excretion during severe hyperphosphatemia. Finally, acetazolamide may have a role in the treatment of Meniere’s disease, nephrogenic diabetes insipidus, idiopathic intracranial hypertension, and Kleine-Levin syndrome (episodes of hypersomnia and cognitive and behavioral abnormalities).
A. Hyperchloremic Metabolic Acidosis
Acidosis predictably results from chronic reduction of body HCO3− stores by carbonic anhydrase inhibitors (Table 15–2) and limits the diuretic efficacy of these drugs to 2 or 3 days. Unlike the diuretic effect, acidosis persists as long as the drug is continued.
Phosphaturia and hypercalciuria occur during the bicarbonaturic response to inhibitors of carbonic anhydrase. Renal excretion of solubilizing factors (eg, citrate) may also decline with chronic use. Calcium phosphate salts are relatively insoluble at alkaline pH, which means that the potential for renal stone formation from these salts is enhanced.
C. Renal Potassium Wasting
Potassium wasting can occur because the increased Na+ presented to the collecting tubule (with HCO3−) is partially reabsorbed, increasing the lumen-negative electrical potential in that segment and enhancing K+ secretion. This effect can be counteracted by simultaneous administration of potassium chloride or a K+-sparing diuretic. Potassium wasting is theoretically a problem with any diuretic that increases Na+ delivery to the collecting tubule.
In addition to potassium wasting, carbonic anhydrase inhibitors can lead to phosphorus wasting, and even symptomatic hypophosphatemia has been reported with these agents. Therefore, both serum potassium and serum phosphorus should be monitored in patients who are being treated chronically with these agents.
Drowsiness and paresthesias are common following large doses of acetazolamide. Carbonic anhydrase inhibitors may accumulate in patients with renal failure, leading to nervous system toxicity. Hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis) may also occur.
Carbonic anhydrase inhibitor–induced alkalinization of the urine decreases urinary excretion of NH4+ (by converting it to rapidly reabsorbed NH3) and may contribute to the development of hyperammonemia and hepatic encephalopathy in patients with cirrhosis.
SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITORS
In the normal individual, the proximal convoluted tubule reabsorbs almost all of the glucose filtered by the glomeruli. Ninety percent of the glucose reabsorption occurs through SGLT2 (Figure 15–2), but inhibiting this transporter using the currently available drugs will result in glucose excretion of only 30–50% of the amount filtered. Although we have known about the proximal tubule sodium/glucose cotransporter for many years, the inhibitors of this transport channel were developed only recently. Four SGLT2 inhibitors (dapagliflozin, canagliflozin, empagliflozin, and ipragliflozin [available in Japan]) are currently available. Angiotensin II has been shown to induce SGLT2 production via the AT1 receptor. Thus, blockade of the renin-angiotensin-aldosterone axis may result in lower SGLT2 availability.
The SGLT2 inhibitors are rapidly absorbed by the gastrointestinal (GI) tract. The elimination half-life of dapagliflozin is 10–12 hours, and up to 70% of the given dose is excreted in the urine in the form of 3-O-glucuronide (only around 2% of the drug is excreted unchanged in the urine). Although the drug levels are higher with more severe renal failure, urinary glucose excretion would also decline as chronic kidney disease worsens. The dose of canagliflozin is recommended not to exceed 100 mg/d with an estimated GFR of 45–59. The drugs are not recommended in patients with more severe renal failure or advanced liver disease. Drug-drug interactions are a consideration with these drugs. For example, concomitant rifampin administration reduces the total exposure to dapagliflozin by 22%.
Clinical Indications and Adverse Reactions
Currently, the only indication for the use of these drugs is as third-line therapy for diabetes mellitus (see Chapter 41). SGLT2 inhibitors will reduce the hemoglobin A1c by 0.5–1.0%, similar to other oral hypoglycemic agents. Even though SGLT2 inhibitors are not indicated for other diagnoses, they do have other minor effects. SGLT2 inhibitors will result in an average weight loss of 3.2 kg versus a weight gain of 1.2 kg with glipizide. It is not clearly established how much of this is due to the diuretic effect, but it is notable that SGLT2 inhibitors also induce a drop in systolic blood pressure by an average of 5.1 mm Hg, compared with an increase in systolic blood pressure of approximately 1 mm Hg after starting sitagliptin. In one study, ipragliflozin resulted in an increase in urine volume from day 1 to day 3. There was a 0.7-kg decrease in body weight by day 3 compared to day 1. Both urine sodium and urine potassium excretion increased with the use of ipragliflozin, but the serum concentrations of both electrolytes remained stable. Thus, it is likely that at least part of the weight loss is due to the diuretic effect of the drugs. Recently there have also been reports of acute kidney injury (AKI) with these drugs. At this point, it is unclear how much the diuretic and blood pressure-lowering effects of these drugs contribute to the reported AKI.
SGLT2 inhibitor therapy is associated with a low incidence of hypoglycemia (3.5% versus 40.8% with glipizide). There is a sixfold increased incidence of genital fungal infection in women and a slightly higher risk of urinary tract infections (8.8% versus 6.1%). All of these agents have been shown to have no or minimal effects on serum electrolyte concentrations.
Loop diuretics selectively inhibit NaCl reabsorption in the TAL. Because of the large NaCl absorptive capacity of this segment and the fact that the diuretic action of these drugs is not limited by development of acidosis, as is the case with the carbonic anhydrase inhibitors, loop diuretics are the most efficacious diuretic agents currently available.
The two prototypical drugs of this group are furosemide and ethacrynic acid (Table 15–4). The structures of these diuretics are shown in Figure 15–7. In addition to furosemide, bumetanide and torsemide are sulfonamide-based loop diuretics.
TABLE 15–4Typical dosages of loop diuretics.
Two loop diuretics. The shaded methylene group on ethacrynic acid is reactive and may combine with free sulfhydryl groups.
Ethacrynic acid—not a sulfonamide derivative—is a phenoxyacetic acid derivative containing adjacent ketone and methylene groups (Figure 15–7). The methylene group (shaded in figure) forms an adduct with the free sulfhydryl group of cysteine. The cysteine adduct appears to be the active form of the drug.
Organic mercurial diuretics also inhibit salt transport in the TAL but are no longer used because of their toxicity.
The loop diuretics are rapidly absorbed. They are eliminated by the kidney by glomerular filtration and tubular secretion. Absorption of oral torsemide is more rapid (1 hour) than that of furosemide (2–3 hours) and is nearly as complete as with intravenous administration. Bumetanide pharmacokinetics are similar to those of torsemide, but bumetanide is a much more potent loop diuretic. The duration of effect for furosemide is usually 2–3 hours. The effect of torsemide lasts 4–6 hours. Half-life depends on renal function. Since loop agents act on the luminal side of the tubule, their diuretic activity correlates with their secretion by the proximal tubule. Reduction in the secretion of loop diuretics may result from simultaneous administration of agents such as NSAIDs or probenecid, which compete for weak acid secretion in the proximal tubule. Metabolites of ethacrynic acid and furosemide have been identified, but it is not known whether they have any diuretic activity. Torsemide has at least one active metabolite with a half-life considerably longer than that of the parent compound. Because of the variable bioavailability of furosemide and the more consistent bioavailability of torsemide and bumetanide, the equivalent dosages of these agents are unpredictable, but estimates are presented in Table 15–5.
TABLE 15–5Relative potency of loop diuretics.
Loop diuretics inhibit NKCC2, the luminal Na+/K+/2Cl− transporter in the TAL of Henle’s loop. By inhibiting this transporter, the loop diuretics reduce the reabsorption of NaCl and also diminish the lumen-positive potential that comes from K+ recycling (Figure 15–3). This positive potential normally drives divalent cation reabsorption in the TAL (Figure 15–3), and by reducing this potential, loop diuretics cause an increase in Mg2+ and Ca2+ excretion. Prolonged use can cause significant hypomagnesemia in some patients. Since vitamin D–induced intestinal absorption and parathyroid hormone–induced renal reabsorption of Ca2+ can be increased, loop diuretics do not generally cause hypocalcemia. However, in disorders that cause hypercalcemia, Ca2+ excretion can be enhanced by treatment with loop diuretics combined with saline infusion.
Loop diuretics have also been shown to induce expression of the cyclooxygenase COX-2, which participates in the synthesis of prostaglandins from arachidonic acid. At least one of these prostaglandins, PGE2, inhibits salt transport in the TAL and thus participates in the renal actions of loop diuretics. NSAIDs (eg, indomethacin), which blunt cyclooxygenase activity, can interfere with the actions of loop diuretics by reducing prostaglandin synthesis in the kidney. This interference is minimal in otherwise normal subjects but may be significant in patients with nephrotic syndrome or hepatic cirrhosis.
Loop agents have direct effects on blood flow through several vascular beds. Furosemide increases renal blood flow via prostaglandin actions on kidney vasculature. Both furosemide and ethacrynic acid have also been shown to reduce pulmonary congestion and left ventricular filling pressures in heart failure before a measurable increase in urinary output occurs. These effects on peripheral vascular tone are also due to release of renal prostaglandins that are induced by the diuretics.
Clinical Indications & Dosage
The most important indications for the use of the loop diuretics include acute pulmonary edema and other edematous conditions. Many times the treatment of the fluid overload will also serve as an effective anti-hypertensive agent, especially in the presence of renal insufficiency. The use of loop diuretics in these conditions is discussed below in Clinical Pharmacology of Diuretic Agents. Other indications for loop diuretics include hypercalcemia, hyperkalemia, acute renal failure, and anion overdose.
In mild hyperkalemia—or after acute management of severe hyperkalemia by other measures—loop diuretics can significantly enhance urinary excretion of K+. This response is enhanced by simultaneous NaCl and water administration.
Loop agents can increase the rate of urine flow and enhance K+ excretion in acute renal failure. However, they cannot prevent or shorten the duration of renal failure. Loop agents can actually worsen cast formation in myeloma and light-chain nephropathy because increased distal Cl− concentration enhances secretion of Tamm-Horsfall protein, which then aggregates with myeloma Bence Jones proteins.
Loop diuretics are useful in treating toxic ingestions of bromide, fluoride, and iodide, which are reabsorbed in the TAL. Saline solution must be administered to replace urinary losses of Na+ and to provide Cl−, so as to avoid extracellular fluid volume depletion.
A. Hypokalemic Metabolic Alkalosis
By inhibiting salt reabsorption in the TAL, loop diuretics increase Na+ delivery to the collecting duct. Increased Na+ delivery leads to increased secretion of K+ and H+ by the duct, causing hypokalemic metabolic alkalosis (Table 15–2). This toxicity is very common and is a function of the magnitude of the diuresis and can be reversed by K+ replacement and correction of hypovolemia. At least one study has found that potassium supplementation upon initiation of loop diuretics, irrespective of the serum potassium concentration, will improve survival.
Loop diuretics occasionally cause dose-related hearing loss that is usually reversible. It is most common in patients who have diminished renal function or who are also receiving other ototoxic agents such as aminoglycoside antibiotics.
Loop diuretics can cause hyperuricemia and precipitate attacks of gout. This is caused by hypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule. It may be prevented by using lower doses to avoid development of hypovolemia.
Magnesium depletion is a predictable consequence of the chronic use of loop agents and occurs most often in patients with dietary magnesium deficiency. It can be reversed by administration of oral magnesium preparations.
E. Allergic and Other Reactions
All loop diuretics, with the exception of ethacrynic acid, are sulfonamides. Therefore, skin rash, eosinophilia, and less often, interstitial nephritis are occasional adverse effects of these drugs. This toxicity usually resolves rapidly after drug withdrawal. Allergic reactions are much less common with ethacrynic acid.
Because Henle’s loop is indirectly responsible for water reabsorption by the downstream collecting duct, loop diuretics can cause severe dehydration. Hyponatremia is less common than with the thiazides (see below), but patients who increase water intake in response to hypovolemia-induced thirst can become hyponatremic with loop agents. Loop agents can cause hypercalciuria, which can lead to mild hypocalcemia and secondary hyperparathyroidism. On the other hand, loop agents can have the opposite effect (hypercalcemia) in volume-depleted patients who have another—previously occult—cause for hypercalcemia, such as metastatic breast or squamous cell lung carcinoma. Long-term loop diuretic therapy may worsen thiamine deficiency in patients with heart failure. Intravenous bumetanide administration has rarely caused injection site superficial tenderness of the skin, an effect not seen with other loop diuretics.
Furosemide, bumetanide, and torsemide may exhibit allergic cross-reactivity in patients who are sensitive to other sulfonamides, but this appears to be very rare. Overzealous use of any diuretic is dangerous in hepatic cirrhosis, borderline renal failure, or heart failure.
The thiazide diuretics were discovered in 1957, as a result of efforts to synthesize more potent carbonic anhydrase inhibitors. It subsequently became clear that the thiazides inhibit NaCl, rather than NaHCO3− transport and that their action is predominantly in the DCT, rather than the PCT. Some members of this group retain significant carbonic anhydrase inhibitory activity (eg, chlorthalidone). The prototypical thiazide is hydrochlorothiazide (HCTZ).
Chemistry & Pharmacokinetics
Like carbonic anhydrase inhibitors and three loop diuretics, all of the thiazides have an unsubstituted sulfonamide group (Figure 15–8).
All thiazides can be administered orally, but there are differences in their metabolism. Chlorothiazide, the parent of the group, is not very lipid-soluble and must be given in relatively large doses. It is the only thiazide available for parenteral administration. HCTZ is considerably more potent and should be used in much lower doses (Table 15–6). Chlorthalidone is slowly absorbed and has a longer duration of action. Although indapamide is excreted primarily by the biliary system, enough of the active form is cleared by the kidney to exert its diuretic effect in the DCT. All thiazides are secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid by that system. As a result, thiazide use may blunt uric acid secretion and elevate serum uric acid level.
TABLE 15–6Thiazides and related diuretics. ||Download (.pdf) TABLE 15–6 Thiazides and related diuretics.
|Drug ||Total Daily Oral Dose ||Frequency of Daily Administration |
|Bendroflumethiazide ||2.5–10 mg ||Single dose |
|Chlorothiazide ||0.5–2 g ||Two divided doses |
|Chlorthalidone1 ||25–50 mg ||Single dose |
|Hydrochlorothiazide ||25–100 mg ||Single dose |
|Hydroflumethiazide ||12.5–50 mg ||Two divided doses |
|Indapamide1 ||2.5–10 mg ||Single dose |
|Methyclothiazide ||2.5–10 mg ||Single dose |
|Metolazone1 ||2.5–10 mg ||Single dose |
|Polythiazide ||1–4 mg ||Single dose |
|Quinethazone1 ||25–100 mg ||Single dose |
|Trichlormethiazide ||1–4 mg ||Single dose |
Thiazides inhibit NaCl reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na+/Cl− transporter (NCC). In contrast to the situation in the TAL, in which loop diuretics inhibit Ca2+ reabsorption, thiazides actually enhance Ca2+ reabsorption. This enhancement has been postulated to result from effects in both the proximal and distal convoluted tubules. In the proximal tubule, thiazide-induced volume depletion leads to enhanced Na+ and passive Ca2+ reabsorption. In the DCT, lowering of intracellular Na+ by thiazide-induced blockade of Na+ entry enhances Na+/Ca2+ exchange in the basolateral membrane (Figure 15–4) and increases overall reabsorption of Ca2+. Although thiazides rarely cause hypercalcemia as a result of this enhanced reabsorption, they can unmask hypercalcemia due to other causes (eg, primary hyperparathyroidism, carcinoma, sarcoidosis). Thiazides are sometimes useful in the prevention of calcium-containing kidney stones caused by hypercalciuria. They may also modestly reduce the risk of osteoporotic fractures.
The action of thiazides depends in part on renal prostaglandin production. As described for loop diuretics, the actions of thiazides can also be inhibited by NSAIDs under certain conditions.
Clinical Indications & Dosage
The major indications for thiazide diuretics are (1) hypertension, (2) heart failure, (3) nephrolithiasis due to idiopathic hypercalciuria, and (4) nephrogenic diabetes insipidus (Table 15–6). Use of the thiazides in each of these conditions is described below in Clinical Pharmacology of Diuretic Agents.
A. Hypokalemic Metabolic Alkalosis
These toxicities are similar to those observed with loop diuretics (see previous text and Table 15–2).
B. Impaired Carbohydrate Tolerance
Hyperglycemia may occur in patients who are overtly diabetic or who have even mildly abnormal glucose tolerance tests. It occurs at higher doses of HCTZ (>50 mg/d) and has not been seen with doses of 12.5 mg/d or less. The effect is due to both impaired pancreatic release of insulin and diminished tissue utilization of glucose. Thiazides have a weak, dose-dependent, off-target effect to stimulate ATP-sensitive K+ channels and cause hyperpolarization of beta cells, thereby inhibiting insulin release. This effect is exacerbated by hypokalemia, and thus thiazide-induced hyperglycemia may be partially reversed with correction of hypokalemia.
Thiazides cause a 5–15% increase in total serum cholesterol and low-density lipoproteins (LDLs). These levels may return toward baseline after prolonged use.
Hyponatremia is an important adverse effect of thiazide diuretics. It is caused by a combination of hypovolemia-induced elevation of ADH, reduction in the diluting capacity of the kidney, and increased thirst. It can be prevented by reducing the dose of the drug or limiting water intake. Genetic studies have shown a link between KCNJ1 polymorphism and thiazide-induced hyponatremia.
E. Impaired Uric Acid Metabolism and Gout
Thiazides are the diuretics most associated with development of gout. One large study found that thiazide diuretics only increase the risk of gout in men younger than age 60 years and not in women or older men. The increased risk in this group of patients was found to be only about 1%.
The thiazides are sulfonamides and share cross-reactivity with other members of this chemical group. Photosensitivity or generalized dermatitis occurs rarely. Serious allergic reactions are extremely rare but do include hemolytic anemia, thrombocytopenia, and acute necrotizing pancreatitis.
Weakness, fatigability, and paresthesias similar to those of carbonic anhydrase inhibitors may occur. Impotence has been reported but is probably related to volume depletion. Cases of acute angle-closure glaucoma from hyponatremia caused by thiazide diuretics have been reported.
Excessive use of any diuretic is dangerous in patients with hepatic cirrhosis, borderline renal failure, or heart failure (see text that follows).
Potassium-sparing diuretics prevent K+ secretion by antagonizing the effects of aldosterone in collecting tubules. Inhibition may occur by direct pharmacologic antagonism of mineralocorticoid receptors (spironolactone, eplerenone) or by inhibition of Na+ influx through ion channels in the luminal membrane (amiloride, triamterene). Finally, ularitide (recombinant urodilatin), which is currently still under investigation, blunts Na+ uptake and Na+/K+-ATPase in collecting tubules and increases GFR through its vascular effects. Nesiritide, which is available for intravenous use only, increases GFR and blunts Na+ reabsorption in both proximal and collecting tubules.
Chemistry & Pharmacokinetics
The structures of spironolactone and amiloride are shown in Figure 15–9.
Spironolactone is a synthetic steroid that acts as a competitive antagonist to aldosterone. Onset and duration of its action are determined substantially by the active metabolites canrenone and 7-α-spirolactone, which are produced in the liver and have long half-lives (12–20 and approximately 14 hours, respectively). Spironolactone binds with high affinity and potently inhibits the androgen receptor, which is an important source of side effects in males (notably, gynecomastia and decreased libido). Eplerenone is a spironolactone analog with much greater selectivity for the mineralocorticoid receptor. It is several hundredfold less active on androgen and progesterone receptors than spironolactone, and therefore, eplerenone has considerably fewer adverse effects (eg, gynecomastia). Finerenone is a new investigational agent in this class. It is a nonsteroidal mineralocorticoid antagonist that reduces nuclear accumulation of mineralocorticoid receptors more efficiently than spironolactone. Like eplerenone, it binds less avidly to the androgen and progesterone receptors. Finerenone accumulates similarly in the heart and the kidneys, whereas eplerenone has three times higher drug concentration in the kidney than the heart and spironolactone is even more preferentially concentrated in the kidneys. Because of this effect, finerenone may prove to be useful for cardioprotection. Finerenone results in less hyperkalemia than spironolactone or eplerenone for poorly understood reasons but possibly from its decreased tendency to accumulate in the kidneys. It also does not have as great a blood pressure-lowering effect as spironolactone or eplerenone. DSR-71167 is an investigational agent in this class that is believed to have carbonic anhydrase inhibitory activity in addition to antimineralocorticoid activity and is thus less likely to cause hyperkalemia.
Amiloride and triamterene are direct inhibitors of Na+ influx in the CCT. Triamterene is metabolized in the liver, but renal excretion is a major route of elimination for the active form and the metabolites. Because triamterene is extensively metabolized, it has a shorter half-life and must be given more frequently than amiloride (which is not metabolized).
Potassium-sparing diuretics reduce Na+ absorption in the collecting tubules and ducts (Figure 15-5). Potassium absorption (and K+ secretion) at this site is regulated by aldosterone, as described above. Aldosterone antagonists interfere with this process. Similar effects are observed with respect to H+ handling by the intercalated cells of the collecting tubule, in part explaining the metabolic acidosis seen with aldosterone antagonists (Table 15–2).
Spironolactone and eplerenone bind to mineralocorticoid receptors and blunt aldosterone activity. Amiloride and triamterene do not block aldosterone but instead directly interfere with Na+ entry through the epithelial Na+ channels (ENaC; Figure 15–5) in the apical membrane of the collecting tubule. Since K+ secretion is coupled with Na+ entry in this segment, these agents are also effective K+-sparing diuretics.
The actions of the aldosterone antagonists depend on renal prostaglandin production. The actions of K+-sparing diuretics can be inhibited by NSAIDs under certain conditions.
Clinical Indications & Dosage
TABLE 15–7Potassium-sparing diuretics and combination preparations. ||Download (.pdf) TABLE 15–7 Potassium-sparing diuretics and combination preparations.
Potassium-sparing diuretics are most useful in states of mineralocorticoid excess or hyperaldosteronism (also called aldosteronism), due either to primary hypersecretion (Conn’s syndrome, ectopic adrenocorticotropic hormone production) or secondary hyperaldosteronism (evoked by heart failure, hepatic cirrhosis, nephrotic syndrome, or other conditions associated with diminished effective intravascular volume). Use of diuretics such as thiazides or loop agents can cause or exacerbate volume contraction and may cause secondary hyperaldosteronism. In the setting of enhanced mineralocorticoid secretion and excessive delivery of Na+ to distal nephron sites, renal K+ wasting occurs. Potassium-sparing diuretics of either type may be used in this setting to blunt the K+ secretory response.
It has also been found that low doses of eplerenone (25–50 mg/d) may interfere with some of the fibrotic and inflammatory effects of aldosterone. By doing so, it can slow the progression of albuminuria in diabetic patients. It is notable that eplerenone has been found to reduce myocardial perfusion defects after myocardial infarction. In one clinical study, eplerenone reduced mortality rate by 15% (compared with placebo) in patients with mild to moderate heart failure after myocardial infarction.
Liddle’s syndrome is a rare autosomal dominant disorder that results in activation of sodium channels in the cortical collecting ducts, causing increased sodium reabsorption and potassium secretion by the kidneys. Amiloride has been shown to be of benefit in this condition, while spironolactone lacks efficacy. Amiloride is also useful for treatment of nephrogenic diabetes insipidus although only studied in patients with lithium-induced diabetes insipidus.
Unlike most other diuretics, K+-sparing diuretics reduce urinary excretion of K+ (Table 15–2) and can cause mild, moderate, or even life-threatening hyperkalemia. The risk of this complication is greatly increased by renal disease (in which maximal K+ excretion may be reduced) or by the use of other drugs that reduce or inhibit renin (β blockers, NSAIDs, aliskiren) or angiotensin II activity (angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor inhibitors). Since most other diuretic agents lead to K+ losses, hyperkalemia is more common when K+-sparing diuretics are used as the sole diuretic agent, especially in patients with renal insufficiency. With fixed-dosage combinations of K+-sparing and thiazide diuretics, the thiazide-induced hypokalemia and metabolic alkalosis are ameliorated. However, because of variations in the bioavailability of the components of fixed-dosage forms, the thiazide-associated adverse effects often predominate. Therefore, it is generally preferable to adjust the doses of the two drugs separately.
B. Hyperchloremic Metabolic Acidosis
By inhibiting H+ secretion in parallel with K+ secretion, the K+-sparing diuretics can cause acidosis similar to that seen with type IV renal tubular acidosis.
Synthetic steroids may cause endocrine abnormalities by actions on other steroid receptors. Gynecomastia, impotence, and benign prostatic hyperplasia (very rare) have been reported with spironolactone. Such effects have not been reported with eplerenone, presumably because it is much more selective than spironolactone for the mineralocorticoid receptor and virtually inactive on androgen or progesterone receptors.
The combination of triamterene with indomethacin has been reported to cause acute renal failure. This has not been reported with other K+-sparing diuretics.
Triamterene is only slightly soluble and may precipitate in the urine, causing kidney stones.
Potassium-sparing agents can cause severe, even fatal, hyperkalemia in susceptible patients. Patients with chronic renal insufficiency are especially vulnerable and should rarely be treated with these diuretics. Oral K+ administration should be discontinued if K+-sparing diuretics are administered. Concomitant use of other agents that blunt the renin-angiotensin system (β blockers, ACE inhibitors, angiotensin receptor blockers) increases the likelihood of hyperkalemia. Patients with liver disease may have impaired metabolism of triamterene and spironolactone, so dosing must be carefully adjusted. Strong CYP3A4 inhibitors (eg, erythromycin, fluconazole, diltiazem, and grapefruit juice) can markedly increase blood levels of eplerenone, but not spironolactone.
AGENTS THAT ALTER WATER EXCRETION (AQUARETICS)
The proximal tubule and descending limb of Henle’s loop are freely permeable to water (Table 15–1). Any osmotically active agent that is filtered by the glomerulus but not reabsorbed causes water to be retained in these segments and promotes a water diuresis. Such agents can be used to reduce intracranial pressure and to promote prompt removal of renal toxins. The prototypic osmotic diuretic is mannitol. Glucose is not used clinically as a diuretic but frequently causes osmotic diuresis (glycosuria) in patients with hyperglycemia.
Mannitol is poorly absorbed by the GI tract, and when administered orally, it causes osmotic diarrhea rather than diuresis. For systemic effect, mannitol must be given intravenously. Mannitol is not metabolized and is excreted by glomerular filtration within 30–60 minutes, without any important tubular reabsorption or secretion. It must be used cautiously in patients with even mild renal insufficiency (see below).
Osmotic diuretics have their major effect in the proximal tubule and the descending limb of Henle’s loop. Through osmotic effects, they also oppose the action of ADH in the collecting tubule. The presence of a nonreabsorbable solute such as mannitol prevents the normal absorption of water by interposing a countervailing osmotic force. As a result, urine volume increases. The increase in urine flow decreases the contact time between fluid and the tubular epithelium, thus reducing Na+ as well as water reabsorption. The resulting natriuresis is of lesser magnitude than the water diuresis, leading eventually to excessive water loss and hypernatremia.
Clinical Indications & Dosage
Reduction of Intracranial and Intraocular Pressure
Osmotic diuretics alter Starling forces so that water leaves cells and reduces intracellular volume. This effect is used to reduce intracranial pressure in neurologic conditions and to reduce intraocular pressure before ophthalmologic procedures. A dose of 1–2 g/kg mannitol is administered intravenously. Intracranial pressure, which must be monitored, should fall in 60–90 minutes. At times the rapid lowering of serum osmolality at initiation of dialysis (from removal of uremic toxins) results in symptoms. Many nephrologists also use mannitol to prevent adverse reactions when first starting patients on hemodialysis. The evidence for efficacy in this setting is limited.
A. Extracellular Volume Expansion
Mannitol is rapidly distributed in the extracellular compartment and extracts water from cells. Prior to the diuresis, this leads to expansion of the extracellular volume and hyponatremia. This effect can complicate heart failure and may produce florid pulmonary edema. Headache, nausea, and vomiting are commonly observed in patients treated with osmotic diuretics.
B. Dehydration, Hyperkalemia, and Hypernatremia
Excessive use of mannitol without adequate water replacement can ultimately lead to severe dehydration, free water losses, and hypernatremia. As water is extracted from cells, intracellular K+ concentration rises, leading to cellular losses and hyperkalemia. These complications can be avoided by careful attention to serum ion composition and fluid balance.
When used in patients with severe renal impairment, parenterally administered mannitol cannot be excreted and is retained in the blood. This causes osmotic extraction of water from cells, leading to hyponatremia without a decrease in serum osmolality.
Acute renal failure has been well described with use of mannitol. The effect is thought to be mediated by the increase in osmolality. The incidence of acute kidney injury with mannitol use has been estimated to be 6–7% of patients who receive the drug.
ANTIDIURETIC HORMONE (ADH, VASOPRESSIN) AGONISTS
Vasopressin and desmopressin are used in the treatment of central diabetes insipidus. They are discussed in Chapter 37. Their renal action appears to be mediated primarily via V2 ADH receptors, although V1a receptors may also be involved.
ANTIDIURETIC HORMONE ANTAGONISTS
A variety of medical conditions, including congestive heart failure (CHF) and the syndrome of inappropriate ADH secretion (SIADH), cause water retention as a result of excessive ADH secretion. Patients with CHF who are on diuretics frequently develop hyponatremia secondary to excessive ADH secretion.
Until recently, two nonselective agents, lithium (see Chapter 29) and demeclocycline (a tetracycline antimicrobial drug discussed in Chapter 44), were used for their well-known interference with ADH activity. The mechanism for this interference has not been completely determined for either of these agents. Demeclocycline is used more often than lithium because of the many adverse effects of lithium administration. However, demeclocycline is now being rapidly replaced by several specific ADH receptor antagonists (vaptans), which have yielded encouraging clinical results.
There are three known vasopressin receptors, V1a, V1b, and V2. V1 receptors are expressed in the vasculature and CNS, while V2 receptors are expressed specifically in the kidney. Conivaptan (currently available only for intravenous use) exhibits activity against both V1a and V2 receptors (see below). The oral agents tolvaptan, lixivaptan, mozavaptan, and satavaptan are selectively active against the V2 receptor. Lixivaptan, mozavaptan, and satavaptan are still under clinical investigation, but tolvaptan, which is approved by the US Food and Drug Administration (FDA), is very effective in treatment of hyponatremia and as an adjunct to standard diuretic therapy in patients with CHF.
The half-lives of conivaptan and demeclocycline are 5–10 hours, while that of tolvaptan is 12–24 hours.
Antidiuretic hormone antagonists inhibit the effects of ADH in the collecting tubule. Conivaptan and tolvaptan are direct ADH receptor antagonists, while both lithium and demeclocycline reduce ADH-induced cAMP by unknown mechanisms.
Clinical Indications & Dosage
A. Syndrome of Inappropriate ADH Secretion
Antidiuretic hormone antagonists are used to manage SIADH when water restriction has failed to correct the abnormality. This generally occurs in the outpatient setting, where water restriction cannot be enforced, but can occur in the hospital when large quantities of intravenous fluid are needed for other purposes. Demeclocycline (600–1200 mg/d) or tolvaptan (15–60 mg/d) can be used for SIADH. Appropriate plasma levels of demeclocycline (2 mcg/mL) should be maintained by monitoring, but tolvaptan levels are not routinely monitored. Unlike demeclocycline or tolvaptan, conivaptan is administered intravenously and is not suitable for chronic use in outpatients.
B. Other Causes of Elevated Antidiuretic Hormone
Antidiuretic hormone is also elevated in response to diminished effective circulating blood volume, as often occurs in heart failure. Due to the elevated ADH levels, hyponatremia may result. As in the management of SIADH, water restriction is frequently the treatment of choice. In patients with heart failure, this approach is often unsuccessful in view of increased thirst and the large number of oral medications being used. For patients with heart failure, intravenous conivaptan may be particularly useful because it has been found that the blockade of V1a receptors by this drug leads to decreased peripheral vascular resistance and increased cardiac output.
C. Autosomal Dominant Polycystic Kidney Disease
Cyst development in polycystic kidney disease is thought to be mediated through cAMP. Vasopressin is a major stimulus for cAMP production in the kidney. It is hypothesized that inhibition of V2 receptors in the kidney might delay the progression of polycystic kidney disease. In a large multicenter prospective trial, tolvaptan was able to reduce the increase in kidney size and slow progression of kidney failure over a 3-year follow-up period. In this trial, however, the tolvaptan group experienced a 9% incidence of abnormal liver function test results compared with 2% in the placebo group. This led to discontinuation of the drug in some patients.
A. Nephrogenic Diabetes Insipidus
If serum Na+ is not monitored closely, any ADH antagonist can cause severe hypernatremia and nephrogenic diabetes insipidus. If lithium is being used for a psychiatric disorder, nephrogenic diabetes insipidus can be treated with a thiazide diuretic or amiloride (see Diabetes Insipidus, below).
Both lithium and demeclocycline have been reported to cause acute renal failure. Long-term lithium therapy may also cause chronic interstitial nephritis.
Dry mouth and thirst are common with many of these drugs. Tolvaptan may cause hypotension. Multiple adverse effects associated with lithium therapy have been found and are discussed in Chapter 29. Demeclocycline should be avoided in patients with liver disease (see Chapter 44) and in children younger than 12 years. Tolvaptan may also cause an elevation in liver function tests and is relatively contraindicated in patients with liver disease.
Medullary urine concentration depends in large part on urea movement in the kidney. Two families of urea transporters have been described. UT-A is present in inner medullary collecting duct cells and the thin descending limb of Henle. UT-B is present in the descending vasa recta and several extrarenal tissues. Inhibitors of both UT-A and UT-B (eg, PU-14) have been developed and are currently in preclinical studies. These agents are aquaretics that increase urea and water excretion but not sodium excretion. Urea transport inhibitors have been shown to blunt the increase in urine osmolality seen after desmopressin administration. These agents may prove to be useful in edematous states and even in SIADH; however, their potential clinical role as compared to that of vaptans remains to be established.
Some patients are refractory to the usual dose of loop diuretics or become refractory after an initial response. Since these agents have a short half-life (2–6 hours), refractoriness may be due to an excessive interval between doses. Renal Na+ retention may be greatly increased during the time period when the drug is no longer active. It was hoped that continuous loop diuretic infusions would be useful in treating patients with heart failure and diuretic resistance, but one high-quality study did not show a benefit for continuous loop diuretic infusion as opposed to bolus doses.
However, after the dosing interval for loop agents is minimized or the dose is maximized, the use of two drugs acting at different nephron sites may exhibit dramatic synergy. Loop agents and thiazides in combination often produce diuresis when neither agent acting alone is even minimally effective. There are several reasons for this phenomenon.
First, salt reabsorption in either the TAL or the DCT can increase when the other is blocked. Inhibition of both can therefore produce more than an additive diuretic response. Second, thiazide diuretics often produce a mild natriuresis in the proximal tubule that is usually masked by increased reabsorption in the TAL. The combination of loop diuretics and thiazides can therefore reduce Na+ reabsorption, to some extent, from all three segments.
Metolazone is the thiazide-like drug usually used in patients refractory to loop agents alone, but it is likely that other thiazides at equipotent doses would be just as effective. Moreover, metolazone is available only in an oral preparation, whereas chlorothiazide can be given parenterally.
The combination of loop diuretics and thiazides can mobilize large amounts of fluid, even in patients who have not responded to single agents. Therefore, close hemodynamic monitoring is essential. Routine outpatient use is not recommended but may be possible with extreme caution and close follow-up. Furthermore, K+ wasting is extremely common and may require parenteral K+ administration with careful monitoring of fluid and electrolyte status. The first large-scale randomized controlled trial of combination loop and thiazide diuretic therapy in patients with heart failure is currently under way in the CLOROTIC (Combination of Loop with Thiazide-type Diuretics in Patients with Decompensated Heart Failure) trial. Clinical experience suggests that in outpatients, adverse effects of thiazides as add-on therapy to loop diuretics can be mitigated by infrequent low-dose therapy. Add-on diuretic therapy with metolazone is started at 2.5 mg weekly and titrated up slowly as needed, with close monitoring of the patient’s blood pressure and serum potassium concentration.
POTASSIUM-SPARING DIURETICS & PROXIMAL TUBULE DIURETICS, LOOP AGENTS, OR THIAZIDES
Hypokalemia often develops in patients taking carbonic anhydrase inhibitors, loop diuretics, or thiazides. This can usually be managed by dietary NaCl restriction or by taking dietary KCl supplements. When hypokalemia cannot be managed in this way, the addition of a K+-sparing diuretic can significantly lower K+ excretion. Although this approach is generally safe, it should be avoided in patients with renal insufficiency and in those receiving angiotensin antagonists such as ACE inhibitors, in whom life-threatening hyperkalemia can develop in response to K+-sparing diuretics.