**7. Epithelial sodium channel blockers**

ENaC blockers are potassium-sparing compounds with weak diuretic properties. Both amiloride and triamterene are treatment of choice in the Liddle syndrome, but are relatively uneffective in essential hypertension when used as monotherapy and can be useful when used in combination with other types of diuretics that cause hypokalemia such as thiazides and loop diuretics.

No studies have evaluated the effects of ENaC blockers in monotherapy in patients with essential hypertension. Four studies with amiloride and 2 studies with triamterene have evaluated the dose-related blood pressure efficacy of these drugs when added, as a second antihypertensive agent, to hydrochlorothiazide or chlorthalidone (Heran et al., 2010).

## **7.1 Amiloride**

80 Antihypertensive Drugs

patients on conventional treatment and, after 12 months, the eplerenone-induced improvement of diastolic function was associated with a significantly slower increase in plasma procollagen levels. Both studies on systolic and diastolic heart failure were conducted

Consistent with previous findings using spironolactone, eplerenone has been demonstrated to confer renal protection independent of its effects on blood pressure. Eplerenone was administered in doses of 50 and 100 mg/day to patients with type 2 diabetes and albuminuria who were already treated with an ACE inhibitor. After 4, 8, and 12 weeks, both doses of eplerenone induced significant reduction of urinary protein losses as compared to placebo, whereas blood pressure levels did not differ during follow-up. Effects of the two

Eplerenone has been repeatedly tested in patients with mild to moderate essential hypertension. One uncontrolled open-label study and many randomized controlled trials have documented the antihypertensive effect of eplerenone when compared to either placebo or other classes of antihypertensive agents. Controlled studies have compared the blood pressure lowering effects of eplerenone at doses comprised form 50 to 400 mg/day with those of either placebo, enalapril, losartan, amlodipine, or spironolactone. In these studies, follow-up duration was from 2 to 14 months. In all studies, eplerenone was more effective than placebo in reducing blood pressure, in two studies it was more potent than losartan, and in the remaining studies the hypotensive effects were comparable to those of enalapril, amlodipine, and spironolactone. Similar to spironolactone, none of these studies reported results for hard cardiovascular endpoints including mortality and major cardiovascular events and therefore there is no evidence that eplerenone improves

Eplerenone has been demonstrated to be beneficial also on hypertension-related subclinical organ damage. In the 4-E Left Ventricular Hypertrophy Study, regression of left ventricular hypertrophy was compared in essential hypertensive patients who were treated with eplerenone, enalapril, or their combination for 9 months. Left ventricular mass index decreased significantly and comparably in patients treated with eplerenone or enalapril, whereas the combination of the two agents showed additive effects on left ventricular mass reduction. In other studies, eplerenone was reported to be more effective than amlodipine,

Despite eplerenone has a satisfactory tolerability and safety profile even at the highest doses that have been clinically tested (200 mg/day), its effects on blood pressure in essential

ENaC blockers are potassium-sparing compounds with weak diuretic properties. Both amiloride and triamterene are treatment of choice in the Liddle syndrome, but are relatively uneffective in essential hypertension when used as monotherapy and can be useful when used in combination with other types of diuretics that cause hypokalemia such as thiazides

hypertension and primary aldosteronism are inferior to those of spironolactone.

with doses of eplerenone (from 25 to 50 mg/day) that did not lower blood pressure.

doses of eplerenone were comparable (Epstein, 2003).

cardiovascular outcomes in hypertensive patients.

**7. Epithelial sodium channel blockers** 

and loop diuretics.

enalapril, or losartan in decreasing urinary albumin excretion.

**6.2.1 Essential hypertension** 

Amiloride is a selective blocker of the ENaC. It is actively secreted by cationic carriers in the proximal tubule, reaching its active site at the distal tubule. At this level, amiloride indirectly antagonizes the effects of aldosterone on sodium-potassium exchange leading to increased sodium excretion with relative potassium retention. Amiloride is cleared by the kidney and can accumulate in patients with impaired renal function. Therefore, the dosage should be reduced when the glomerular filtration rate is below 50 ml/min.

No studies have evaluated amiloride as monotherapy in patients with essential hypertension. Amiloride is administered in patients with essential hypertension usually in combination with thiazide diuretics. Amiloride can also be used in patients with primary aldosteronism when spironolactone is not tolerated. Although studies that have tested amiloride as an antihypertensive agents have reported good tolerability, particular caution is required in patients with renal failure or in patients treated with blockers of the reninangiotensin system because of the risk of hyperkalemia.

Data on use of amiloride (from 2.5 to 5 mg/day) in combination with hydrochlorothiazide are insufficient to demonstrate a significant difference between treatment with the combination and hydrochlorothiazide alone. Therefore current evidence does not support any effect of low doses of amiloride on blood pressure. No trials evaluating doses of amiloride higher than 5 mg/day have been performed and therefore a dose-response relationship with the hypotensive effect can not be demonstrated. No effects of amiloride on pulse pressure or blood pressure variability could be demonstrated in the studies that have employed this agent in the treatment of hypertension.

There are no appropriately designed studies that have tested the effects of amiloride in other disease conditions. In primary aldosteronism experiences are mainly anedoctal and the doses of this drug to use in this context have never been defined with precision. No studies have been performed to test the effects of amiloride on subclinical hypertensive organ damage, heart failure, and proteinuria.

## **7.2 Triamterene**

Similar to amiloride, triamterene blocks the ENaC in the distal tubular site of the nephron. Triamterene is incompletely absorbed and is transformed to a sulphate-conjugated metabolite. It gains access to the tubular lumen via a cationic transporter in the proximal tubule. Both triamterene and its metabolite accumulate in patients with renal failure. When used alone, triamterene has little effect on blood pressure. Therefore it is usually employed in combination to compensate for the hypokalemic effects of other diuretics.

No studies have evaluated triamterene as monotherapy in patients with essential hypertension. Data on use of triamterene (50 mg/day) in combination with chlorthalidone are insufficient to demonstrate a significant difference between treatment with the

Potassium-Sparing Diuretics in Hypertension 83

increased left ventricular mass and greater risk to develop hypertension. Since CYP11B2 activity is the limiting biochemical step in aldosterone synthesis, its selective inhibition is a good target for prevention of aldosterone untoward effects mediated by both mineralocorticoid receptor-dependent and mineralocorticoid receptor-independent

At present, only two compounds (both synthesized by Novartis®) with selective CYP11B2 inhibitory properties have been tested in animal models and, very recently, in the clinical setting. FAD286 is the D-enantiomer of the fadrozole, an aromatase inhibitor developed to treat advanced breast cancer, that reduces aldosterone levels and increases plasma renin activity in rats fed with either low or high sodium diet. In a transgenic rat model of secondary hypertension in which the angiotensinogen gene is overexpressed and circulating angiotensin II levels are increased, oral administration of FAD286 has reduced mortality by 4 times. In transgenic rats treated with FAD286, cardiac hypertrophy, albuminuria, and histologic evidence of glomerular damage were less frequent than in control animals. Despite very minor effects of FAD286 on blood pressure, its effects on organ damage were

Following promising preclinical results, the first aldosterone synthase inhibitor, LCI699, was tested in two phase-II clinical trials. LCI699 is similar in structure to FAD286 and it has been developed for human use. LCI699 was administered to 14 patients affected by primary aldosteronism and effects were compared to those of placebo. After 2 weeks of treatment, there was a dose-dependent decrease in plasma aldosterone and an increase in 11 deoxycorticosterone, potassium, and adrenocorticotropin levels. Treatment induced mild reduction of 24-h ambulatory systolic blood pressure by (4.1 mm Hg) after 4 weeks. More recently, Calhoun et al. have published the first randomized, double-blind, placebo controlled phase-II trial with LCI699 that was conducted in 524 patients with essential hypertension. In this trial different doses of LCI699 have reduced 24-h ambulatory systolic

blood pressure, but only the highest dose has reduced also diastolic blood pressure.

This work was supported by a research grant of the Pier Silverio Nassimbeni Foundation.

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comparable to those of the angiotensin receptor blocker, losartan.

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**9. Acknowledgments** 

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**10. References** 

combination and chlorthalidone alone. Therefore current evidence does not support any effect of low doses of triamterene on blood pressure. No data are currently available on the effects on blood pressure of higher doses of triamterene and therefore a dose-response relationship with the hypotensive effect can not be demonstrated. No effects of triamterene on pulse pressure or blood pressure variability could be demonstrated in the studies that have employed this agent in the treatment of hypertension. Tolerability and safety profile of triamterene in the studies that have tested this drug were acceptable.

There are no studies that have tested the effects of triamterene in other disease conditions. In primary aldosteronism experiences are mainly anedoctal and the doses of this drug that should be used in this endocrine disorder have never been specifically defined. No studies have been conducted to investigate the effects of triamterene on subclinical hypertensive organ damage, heart failure, and proteinuria.
