**6. Eplerenone**

Eplerenone (Figure 1) has been synthesized in the attempt to obtain a more selective inhibition of the mineralocorticoid receptors to overcome the side effects due to crossreaction of spironolactone and canrenone with androgen receptors. It was synthesized in the Ciba-Geigy laboratories in the mid-80s and was approved in the United States for clinical use in arterial hypertension in 2002.

#### **6.1 Pharmacology**

78 Antihypertensive Drugs

disease, cerebrovascular events, and sustained arrhythmias (Catena et al. 2008). Patients were followed for an average of 7.4 years after surgical removal of an adrenal adenoma or treatment with spironolactone, with a combined end point including myocardial infarction, stroke, any type of revascularization procedure, and sustained arrhythmias. During followup, blood pressure was comparable in the primary aldosteronism and essential hypertension group, and 10 patients in the former group and 19 in the latter group reached the end point. Actuarial analysis of patients treated with surgery vs. spironolactone did not reveal significant difference in the occurrence of the combined end point. In the same cohort of patients, the outcomes of renal function were investigated by measuring the rates of change of glomerular filtration and albuminuria (Sechi et al., 2006). After an initial decline in creatinine clearance, due to correction of the aldosterone-induced intrarenal hemodynamic adaptation, subsequent decrease of glomerular filtration in patients with primary aldosteronism and essential hypertension were comparable. Urinary albumin losses did not differ between patients with primary aldosteronism and essential hypertension during follow-up. Evaluation of renal outcomes in patients with primary aldosteronism who were treated with surgery or spironolactone did not reveal significant difference. These two studies clearly demonstrate that spironolactone has the same therapeutic value as surgery in the treatment of primary

aldosteronism and in the prevention of cardiovascular and renal complications.

**5. Canrenoate** 

**6. Eplerenone** 

with small volumes of distribution.

In addition to excess cardiovascular and renal events as compared to matched patients with essential hypertension, patients with primary aldosteronism are characterized by cardiac, renal, and metabolic subclinical structural and functional abnormalities (Rossi et al., 2008). A number of cross-sectional cardiac ultrasound studies have reported an excess increase of left ventricular mass in patients with primary aldosteronism as compared to other types of hypertensive disease. In a 7-year echocardiographic study it was demonstrated that patients with primary aldosteronism treated with either surgery or spironolactone have significant and comparable decrease of left ventricular mass, although decrease is significant within the first year only after adrenalectomy (Catena et al., 2007). We have already mentioned the effects of spironolactone on correction of albuminuria. These effects are at least in part related to reversal of an intrarenal hemodynamic adaptation to aldosterone excess with a vasodilatory response that has been demonstrated with intrarenal echo-Doppler examination (Sechi et al., 2009).

Canrenone (Figure 1) is one of the two metabolites of spironolactone. It is administered orally as a potassium salt (potassium canrenoate) that is mineralocorticoid receptor-inactive, but it is rapidly transformed to canrenone. Canrenone is water soluble, and this

Potassium canrenoate exerts its hypotensive effect approximately one week after the starting dose. Both canrenone and canrenoate are rapidly absorbed (approximately 80%) after oral administration. Both agents have important plasma protein binding (approximately 90%)

Eplerenone (Figure 1) has been synthesized in the attempt to obtain a more selective inhibition of the mineralocorticoid receptors to overcome the side effects due to crossreaction of spironolactone and canrenone with androgen receptors. It was synthesized in the

characteristic permits intravenous administration when a rapid effect is desired.

Eplerenone was synthesized by replacing the 17-thioacetyl group with a carbomethoxy group in the molecule of spironolactone (Figure 1). The critical feature in the eplerenone molecule however, conferring enhanced mineralocorticoid receptor selectivity is the presence of the epoxide group in the lactone ring. The activity of eplerenone in vitro was assessed in vitro using recombinant steroid receptors. The potency of eplerenone at other steroid receptors was significantly reduced and, unlike previous aldosterone blockers, eplerenone possesses very low activity on the androgen, progesterone, and glucocorticoid receptors.

Oral bioavailability is approximately 95% and meals have no effect on the extent of absorption. Eplerenone does not undergo relevant metabolic first-pass in the liver neither it induces cytochrome P450 activity, although interactions with drugs that are metabolized by cytochrome P450 are not excluded. The two main metabolites of eplerenone (6β-OH eplerenone and open lactone ring) are both mineralocorticoid receptor-inactive. The plasma half-life of eplerenone is approximately 5 hours.

The recommended oral dosing range for eplerenone is from 50 to 100 mg once or twice daily in essential hypertension. No correlations between eplerenone disposal and renal function have been found.

## **6.2 Clinical use**

Eplerenone has come into the clinical arena in the last decade and has been employed to lower blood pressure in essential hypertensive patients. Similar to spironolactone, recent studies have reported beneficial effects of eplerenone in congestive heart failure and renal disease with proteinuria. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) (Pitt et al. 2003) investigated the effects of eplerenone in postmyocardial infarction patients with severely impaired left ventricular function, showing a significant decrease in the mortality rate as compared to patients who received placebo on top of conventional treatment. Recently, these observations have been extended to patients with milder degrees of cardiac dysfunction in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) (Zannad et al., 2011) study. In this study, 2737 patients with NYHA class II cardiac insufficiency and left ventricular ejection fraction of less than 35% were randomized to receive either eplerenone or placebo in addition to conventional treatment. This trial ended prematurely after a median follow-up of 21 months because the composite endpoint of cardiovascular death and hospitalization for heart failure were significantly less frequent in patients who were treated with eplerenone. Thus, eplerenone seems to be beneficial even at the early stages of systolic cardiac failure.

As for spironolactone, the possibility that eplerenone may result beneficial also in patients with HFPSF has been investigated. Forty-four elderly patients with heart failure and left ventricular ejection fraction of more than 45% were randomized to conventional treatment with or without eplerenone and left ventricular function was reassessed with conventional echocardiography and tissue Doppler imaging at 6 and 12 months. In patients who were treated with eplerenone, deceleration time had a significantly greater decrease than in

Potassium-Sparing Diuretics in Hypertension 81

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

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

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 renin-

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

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

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

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

in combination to compensate for the hypokalemic effects of other diuretics.

antihypertensive agent, to hydrochlorothiazide or chlorthalidone (Heran et al., 2010).

should be reduced when the glomerular filtration rate is below 50 ml/min.

angiotensin system because of the risk of hyperkalemia.

employed this agent in the treatment of hypertension.

damage, heart failure, and proteinuria.

**7.2 Triamterene** 

**7.1 Amiloride** 

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

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 doses of eplerenone were comparable (Epstein, 2003).
