Aldosterone receptor blockers spironolactone and canrenone: two multivalent drugs

Abstract

Canrenone is a derivative of spironolactone with lower antiandrogen activity. The drug is used only in few countries and can block all the side effects of aldosterone (ALDO). The drug is effective even in the presence of normal concentrations of ALDO. Mineralcorticoid receptor antagonists block the inflammatory activity of ALDO at the level of target tissues as heart, vessels and mononuclear leukocytes. Canrenone reduces the progression of insulin resistance and of microalbuminuria in type 2 diabetes and other related diseases. Both canrenone and hydrochlorothiazide can enhance the effect of treatment with ACE inhibitors and angiotensin II receptor blockers on microalbuminuria, but ALDO receptor blockers are more active. This different action is due to the fact that only canrenone blocks mineralocorticoid receptors. Serum potassium and renal function should be monitored before and during the treatment. ALDO receptor blockers are recommended in addition to polytherapy for resistant hypertension, but there are no studies on the effect of the drug as first-choice therapy.

Keywords::

• aldosterone
• canrenone
• inflammation
• microalbuminuria
• spironolactone

Spironolactone (SP) and its derivatives are widely used as aldosterone (ALDO) receptor blockers in epithelial cells of the kidney and of other classical target tissues of ALDO, for the treatment of patients with primary aldosteronism, essential hypertension, liver cirrhosis and heart insufficiency. Only recently, SP and its derivatives have been recommended for resistant hypertension as additive treatment when polytherapy is not effective.

In a paper published in 2001 in the Expert Opin Investig Drugs, Doggrell and Brown talked of the SP renaissance after the experimental and clinical evidence that SP or eplerenone can prevent or block the progression of ALDO-induced cardiac fibrosis by a direct vascular and cardiac action [1]. Randomized Aldactone Evaluation Study clearly showed a 30% reduction in risk of death among the SP-treated patients. The addition of SP to the conventional treatment was also able to reduce the time of hospitalization for worsening heart failure (HF) and to improve the symptoms of HF [2]. Other recent clinical trials have shown that SP inhibits cardiac and vascular collagen turnover, improves heart variability, reduces ventricular arrhythmias, improves endothelial dysfunction and dilates blood vessels in human HF, and these effects probably all contribute to the increased survival in HF [3]. In another study, SP was not associated with improved long-term survival in the general HF population, but only in patients enrolled in HF clinics [4]. ALDO receptor blockers, in addition, can improve insulin resistance and the inflammatory state observed in metabolic syndrome and may also be useful in the treatment of portal hypertension and cirrhosis [5].

Most authors have reported the association of sodium load and excess of ALDO as a prerequisite for demonstrating the inflammatory and profibrotic effect of ALDO in animal models, but subsequent clinical evidence has supported the concept that SP can exert its activity even in the presence of normal ALDO concentrations and normal sodium intake. The association of ALDO and sodium load in diseases other than primary aldosteronism is only speculative given that ALDO is suppressed in vivo in patients with volume expansion, for example due to sodium load. In addition, chronic hypersecretion of ALDO produces polyuria due to the escape of the kidney to the action of ALDO. These considerations suggest that SP is effective even in patients with normal ALDO. From these observations it can be speculated that even normal values of ALDO could produce negative effects in predisposed patients, as SP is effective in ameliorating the clinical and biochemical alterations.

Chronic treatment with SP can produce side effects such as hyperkalemia, gynecomastia and menstrual irregularities. The pathogenesis of these side effects is not completely understood. SP acts as androgen receptor antagonist but is also able to directly block the synthesis of both adrenal and gonadal steroids. SP can also enhance aromatase, block 5 α reductase and increase the SHBG. All these effects have been used for treatment of hirsutism and acne alopecia in women, in particular women with polycystic ovary syndrome [6]. In this disease, which is associated with chronic inflammation, ALDO and ALDO/PRA ratio are higher than in control women and therefore SP could reverse both the clinical picture of hyperandrogenism and the inflammatory situation linked to hyperactivity of ALDO [7]. SP also has a progesterone-like or progesterone receptor antagonist in women and this aspect is not clarified at the moment.

These antiandrogen effects, particularly in male patients, have limited the use of SP in patients with hypertension and therefore a lot of studies have been performed in order to find some derivative with lower antiandrogen activity [8]. In some countries canrenone and potassium canrenoate are available and a previous study has demonstrated that the antiandrogen activity of canrenone and potassium canrenoate is much lower than that of SP. Considering that the most important metabolite of SP is canrenone, it has been hypothesized that some methylated metabolites of SP have a powerful anti-mineralocorticoid and antiandrogen activity, thus explaining the higher affinity for mineralocorticoid receptors (MR) of SP, compared to canrenone and eplerenone. Based on these considerations canrenone and eplerenone were introduced as an alternative to SP.

Eplerenone is devoid of antiandrogenic action and is currently used for improving survival of stable patients with left ventricular systolic dysfunction and chronic HF after acute myocardial infarction, and in hypertension alone or associated with other agents. Canrenone is inexpensive, has not limitation to the prescription in the countries where it is available, and has a lower antiandrogenic activity than SP. It is, therefore, a valid alternative to eplerenone. In a previous report canrenone and potassium canrenoate were able to produce antiandrogen effects in patients with liver cirrhosis, but in these patients the metabolism of steroids and drugs is compromised [9].

ALDO receptor blockers should be considered for treatment of hypertension, considering the protective effect of the block of MR in the limitation of side effects due to the inflammatory and fibrotic effect of ALDO. In particular, studies have found a protective action of SP in the genesis and progression of atherosclerosis and of the related cardiovascular complications [10]. However, one must be careful when combining an ACE inhibitor (ACE-I) or an angiotensin II type 1 receptor blocker (ARB) with an ALDO antagonist. ALDO receptor blockers should not be used if the serum potassium is greater than 5.0 mmol/l or the serum creatinine is greater than 2.0 mg/dl in women or 2.5 mg/dl in men.

Another important use of ALDO antagonist is in the delay of progression of kidney glomerular and tubular damage, particularly in patients with chronic diabetes. It is well known that the progression of microalbuminuria is reduced by treatment with ACE-I or ARB and this kind of treatment is widely used for these patients. Diabetes is a chronic disease characterized by a progressive impairment of kidney function measured as an increase in microalbuminuria. Microalbuminuria is also peculiar of other diseases such as chronic hypertension, preeclampsia in the preclinical phase, hypothyroidism and others.

The efficacy of ACE-I and ARB in blocking the progression of microalbuminuria is even more evident in these patients when also other factors such as obesity or hypertension are controlled. ACE-I can have some limitations, such as the onset of caught or the escape of kidney to the action of the drug. It is well known that during ACE-I and ARB, ALDO concentration is reduced but sometimes it later increases due to an escape of the kidney to the block, thus blunting their effect. The ALDO escape during treatment with ACE-I in diabetes has been associated with the deterioration of glomerular filtration rate but this interpretation does not fit with the damage of the iuxtaglomerular apparatus frequently produced in diabetic patients, which should reduce rather than increase ALDO production as a consequence of damage to the iuxtaglomerular apparatus [11].

An interesting result of the study of Fogari is that both hydrochlorothiazide (HCT) and canrenone are able to reduce microalbuminuria when added to conventional treatment with ACE-I or ARB, but canrenone has a more powerful effect [12]. HCT, considering all the physiological effects of ALDO, has two opposite actions: a negative effect due to the stimulation of ALDO synthesis as a consequence of the volume depletion, but also a positive effect due to its diuretic effect and the reduction of blood pressure it causes. Canrenone is able to activate the renin angiotensin ALDO system and has the advantage that it cannot produce an ALDO-like effect being an ALDO receptor blocker. This point is very important since both drugs can further control blood pressure, but while thiazides increase plasma ALDO activating MR, canrenone increases ALDO without activating the receptors. These dichotomous effects have been focused by Ma and coll [13]. These authors found that PAI 1 and other markers of inflammation are increased by HCT and blocked by SP. The amelioration of microalbuminuria with HCT confirms that this effect is not only related to the block of MR but also to the reduction of blood pressure and maybe to the diet and other measures. The more protective action of ALDO receptor blockers in this complication of diabetes could be related also to the known escape to the ACE-I block of ALDO synthesis. A novel application of SP, or better of canrenone, is therefore their use in diabetes independent from the blood pressure levels to prevent the progression of microalbuminuiria and other situations associated with microalbuminuria. The positive effects of ALDO receptor blockers are not confined to the kidney but extend to all the target tissues for ALDO, as ALDO receptors are located not only in the classical targets of ALDO (kidney, colon, salivary glands), but also in several other tissues such as endothelium, heart, hippocampus and, in particular, lymphomonocytes [14]. This last tissue is very important since all inflammatory processes start in the circulation and involve an accumulation of peripheral inflammatory cells in the site. The activation of macrophages leads to cytokine secretion and progression of the phenomenon of inflammation. ALDO effects are not only genomic but also non-genomic and probably the two effects are linked each to other. The most important nonclassical effects are those on sodium proton exchange and intracellular pH. ALDO is able to induce the expression of several markers of inflammation such as PAI-1, NADPH oxidase, fibronectin and TGF-β [15]. Addition or coincubation with canrenone in peripheral mononuclear leukocytes blocks all these effects [16].

Another important effect of ALDO receptor blockers is the amelioration of atherosclerosis as demonstrated in ApoE-knockout animals. The treatment of these animals with SP blocks the entrance of cholesterol and the formation of atheromasia in the vessels. From these considerations it follows that canrenone should not only be used as a potassium-sparing diuretic in hypertension and in primary aldosteronism, but also as an anti-inflammatory agent in patients with inflammatory diseases that are frequently associated with microalbuminuria. These anti-inflammatory effects are evident even in normotensive patients, for example, in polycystic ovary syndrome, where SP can ameliorate both the hirsutism due to its antiandrogen activity and the inflammatory habitus linked to the increased activity of ALDO.

Hans Seley who described the adaptation syndrome emphasized this application in 1953 [17]. He hypothesized that ALDO is the main inflammatory steroid, opposing to the action of cortisol, which is anti-inflammatory. Recent studies have found that canrenone, SP and eplerenone can have a positive effect in many different clinical situations that are associated with inflammation. ALDO receptor blockers are effective in insulin resistance, coriorethinitis, rheumatic diseases and psoriasis. In all these situations, the presence of diabetes and microalbuminuria is very frequent and the use of canrenone could ameliorate not only albuminuria but also all the factors that are linked to a hyperactivity of MR.

ALDO receptor blockers have been neglected for several years due to their side effects but currently they are widely being reconsidered, although there is still some hesitation. Recently, the European Society of Hypertension (ESH) has recommended the use of ALDO receptor blockers only as an additive treatment to the conventional polytherapy in patients with resistant hypertension. In our experience, in many patients with resistant hypertension, the addition of ALDO receptor blockers can reverse hypertension even after withdrawal of other treatments, suggesting that the hypertension was resistant because ALDO receptor blockers were not used.

Considering all the benefits of ALDO receptor blockers in heart, metabolic and kidney dysfunction, it could be of interest to study the effect of ALDO receptor blockers as first-choice treatment for hypertension, even if this kind of treatment is not recommended by the guidelines of ESH and European Society of Cardiology.

Declaration of interest

The authors have no competing interests to declare and have received no funding in preparation of the manuscript.

Acknowledgment

We thank Sophie Armanini for the English revision.