Beneficial Effects Of Spironolactone Research Articles

The rise of counterfeit medication: an emerging threat?

Madam, Heart failure (HF) is a multifaceted clinical syndrome arising from a functional or structural cardiac condition that hampers the adequate filling or expulsion of blood into the systemic circulation. It is estimated that heart failure affects around 26 million people globally and significantly adds to healthcare expenditures on a worldwide scale1. Furthermore, in 2016, approximately 16 percent of deaths in Pakistan were due to heart related disorders. This number grew to 29 percent in 20222. HF can greatly diminish the functional capability of a patient and heighten the risk of mortality. Therefore, it is essential to accurately diagnose and proficiently manage this condition to improve the quality of life of the patient. Spironolactone, the first mineralocorticoid receptor antagonist (MRA) to be developed, is prescribed for the management of hypertension, primary hyperaldosteronism, and peripheral oedema linked to cardiac failure3. When HF occurs and cardiac output decreases, it stimulates the renin-angiotensin-aldosterone system (RAAS) which in turn causes salt and water reabsorption and thus increases venous return to the heart which further contributes to congestive heart failure and heart fails to pump the additional fluid and pooling occurs. Here MRAs are very affective as they inhibit the function of aldosterone and hence fluid retention does not occur. Unfortunately, the beneficial effects of spironolactone do not occur without substantial adverse effects. Firstly, spironolactone is associated with sexual adverse events due to its affinity for androgen and progesterone receptors. There have been reports of male patients experiencing gynecomastia and breast pain. Secondly, spironolactone has been classified as potassium sparing diuretic hence hyperkalemia (defined as serum K+ > 5.5 mEq/L) is a common side effect3. Hyperkalemia can manifest as muscle weakness or paralysis, metabolic acidosis, cardiac conduction abnormalities, and life-threatening cardiac arrhythmias4. These cardiac arrythmias can have serious consequences, including cardiac arrest and stroke. In conclusion heart failure, if not treated immediately, can be fatal. Spironolactone is a drug used for management of heart failure; however, it has some detrimental effects on the cardiovascular system such as development of serious cardiac arrythmias. Hyperkalemia, due to potassium sparing nature of MRAs, is the primary cause of these life-threatening effects thus it is recommended to assess serum potassium levels and renal function of a patient with heart failure before prescribing spironolactone. Moreover, patients who are being treated with spironolactone should be periodically monitored to prevent any casualty.

<p>Spotlight on Spironolactone Oral Suspension for the Treatment of Heart Failure: Focus on Patient Selection and Perspectives</p>

Spironolactone, an antagonist of aldosterone, initially used as a potassium-sparing diuretic, was subsequently shown to be a very effective adjunctive agent in the treatment of patients with heart failure with reduced ejection fraction, by halting the disease progression, with significant beneficial effects on both morbidity and mortality. Other uses comprise resistant hypertension, edema in patients with cirrhosis, and other on- and off-label uses. Recent data indicate that spironolactone also may offer some symptomatic relief in patients with heart failure and preserved ejection fraction. However, a variable percentage of patients, particularly among the aged group, may have difficulty in swallowing or may be unable to swallow tablets and thus are deprived of the benefits of such therapy. In 2017, the FDA approved a liquid suspension formulation of spironolactone, CaroSpir®, which will enable more heart failure and other patients in need of aldosterone inhibition to avail themselves of the protective and beneficial effects of spironolactone. The new drug formulation comes as a banana-flavored oral suspension that contains 25 mg/5 mL of spironolactone, supplied in 4-ounce (118 mL) and 16-ounce (473 mL) bottles. The details of this drug formulation development and the benefits of spironolactone use in patients with heart failure with a focus on patient selection are herein reviewed.

Mechanisms Involved in the Beneficial Effects of Spironolactone after Myocardial Infarction

IntroductionOur objective was to analyze the effect of spironolactone on cardiac remodeling after experimental myocardial infarction (MI), assessed by matricellular proteins levels, cardiac collagen amount and distribution, myocardial tissue metalloproteinase inhibitor-1(TIMP-1) concentration, myocyte hypertrophy, left ventricular architecture, and in vitro and in vivo cardiac function.MethodsWistar rats were assigned to 4 groups: control group, in which animals were submitted to simulated surgery (SHAM group; n=9); group that received spironolactone and in which animals were submitted to simulated surgery (SHAM-S group, n=9); myocardial infarction group, in which animals were submitted to coronary artery ligation (MI group, n=15); and myocardial infarction group with spironolactone supplementation (MI-S group, n=15). The rats were observed for 3 months.ResultsThe MI group had higher values of left cardiac chambers and mass index and lower relative wall thicknesses compared with the SHAM group. In addition, diastolic and systolic functions were worse in the MI groups. However, spironolactone did not influence any of these variables. The MI-S group had a lower myocardial hydroxyproline concentration and myocyte cross-sectional area compared with the MI group. Myocardial periostin and collagen type III were lower in the MI-S group compared with the MI-group. In addition, TIMP-1 concentration in myocardium was higher in the MI-S group compared with the MI group.ConclusionsThe predominant consequence of spironolactone supplementation after MI is related to reductions in collagens, with discrete attenuation of other remodeling variables. Importantly, this effect may be modulated by periostin and TIMP-1 levels.

Role of aldosterone on lung structural remodelling and right ventricular function in congestive heart failure

BackgroundThe mechanisms of benefit of mineralocorticoid receptors antagonists in congestive heart failure (CHF) are still debated. We hypothesized that aldosterone contributes to pulmonary remodelling and right ventricular (RV) dysfunction associated with CHF by stimulation of lung myofibroblasts (MYFs) proliferation.MethodsRats with moderate to large myocardial infarcts (MI) and CHF were studied. Two weeks after MI, spironolactone 100 mg/kg/day (n = 21) or no treatment (n = 24) were given for 3 weeks and compared to sham (n = 8).ResultsInfarct size was similar by ultrasound and pathologic measures in both MI groups.The MI-untreated group developed important lung remodelling with nearly doubling of dry lung weight (p < 0.01), reduced left ventricular (LV) fractional shortening (16 ± 2% vs. 53 ± 1%; mean ± SEM, p < 0.0001), pulmonary hypertension (RV systolic pressure: 40 ± 3 mmHg vs. 27 ± 1 mmHg, p < 0.01) and RV hypertrophy (RV/(LV + septum): 38 ± 3% vs. 24 ± 1%, p < 0.05). Spironolactone had no effect on these parameters and did not improve LV or RV performance (tricuspid annular plane systolic excursion and RV myocardial performance index) measured by echocardiography. CHF induced a restrictive respiratory syndrome with histological lung fibrosis: this was also unaffected by spironolactone. Finally, isolated lung MYFs did not proliferate after exposure to aldosterone.ConclusionAldosterone does not significantly contribute to pulmonary remodelling and RV dysfunction associated with CHF. Other mechanisms are responsible for the beneficial effects of spironolactone in CHF.

Sex difference in cognitive impairment associated with diabetes-mellitus and beneficial effect of spironolactone on this cognitive decline

Sex difference in cognitive impairment associated with diabetes-mellitus and beneficial effect of spironolactone on this cognitive decline

Effect of spironolactone and vitamin E on serum metabolic parameters and insulin resistance in patients with nonalcoholic fatty liver disease

The renin-angiotensin-aldosterone system has been implicated in the pathogenesis of insulin resistance and nonalcoholic fatty liver disease (NAFLD). The beneficial effect of spironolactone in a mouse model with diabetes and NAFLD has recently been reported. The main aim was assessment of the effect of spironolactone on serum metabolic parameters and insulin resistance in patients with NAFLD. This study includes preliminary results of a single-centre randomised controlled trial of treatment with vitamin E (group 1, 10 patients) versus spironolactone plus vitamin E (group 2, 10 patients) in biopsy-proven NAFLD. Serum transaminases, lipids, potassium, sodium, glucose and insulin were measured, and homeostatic model assessment-insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were calculated before and 8( )weeks after baseline assessment. Insulin was decreased within group 2 (15.3 ± 2.7 at baseline vs. 10.3 ± 5.0 at week 8, p = 0.013). Although no difference in glucose was observed, HOMA-IR significantly decreased (4.4 ± 0.9 vs. 2.8 ± 0.5, respectively, p = 0.047). QUICKI was increased, but not statistically significantly. Spironolactone and vitamin E combined therapy seems to exhibit a favourable effect on serum insulin and HOMA-IR in patients with NAFLD. If validated in a large-scale clinical trial, it may prove an inexpensive therapeutic approach for the management of NAFLD patients.

Effect of Spironolactone on Left Ventricular Ejection Fraction and Volumes in Patients With Class I or II Heart Failure

The beneficial effects of spironolactone in chronic heart failure (HF) have been demonstrated in patients with New York Heart Association (NYHA) class III to IV HF. This study examined the effect of spironolactone on left ventricular (LV) function and functional capacity of patients with mild to moderate HF (NYHA class I to II). One hundred sixty-eight patients with NYHA class I to II HF and LV ejection fraction ≤40% were randomized to spironolactone or placebo and assessed by echocardiography, gated single-photon emission computed tomography, technetium-99m sestamibi single-photon emission computed tomographic radionuclide ventriculography, and cardiopulmonary exercise testing at baseline and after 6 months of treatment. In the spironolactone group LV ejection fraction increased from 35.2 ± 0.7% to 39.1 ± 3.5% (p <0.001), with a decrease in LV end-diastolic and end-systolic volumes and myocardial mass and an improvement in LV diastolic filling pattern. Cardiopulmonary exercise testing parameters did not change. In conclusion, administration of spironolactone to patients with NYHA class I to II HF has beneficial effects on LV remodeling and diastolic function.

Aldosterone antagonists: Silver bullet or just sodium excretion and potassium retention?

ACE inhibitors or AT(1) antagonists are powerful therapeutic strategies to slow the progression of renal disease. However, they provide only imperfect protection since they cannot always prevent end-stage renal failure. Innovative approaches are needed to keep patients with chronic kidney disease off dialysis. Blockade of the aldosterone pathway may prove to be such a beneficial therapeutic concept.

Can the dextroenantiomer of the aromatase inhibitor fadrozole be useful for clinical investigation of aldosterone-synthase inhibition?

The beneficial effects of spironolactone, eplerenone, amiloride and potassium in preventing cardiovascular damage in various experimental models of salt-induced hypertension can be dissociated from blood pressure effects, and have drawn attention to the direct genomic and non-genomic actions of aldosterone at the level of the vessels, the heart and the kidneys. Exposure to endogenous aldosterone could be decreased by direct and specific aldosterone-synthase inhibition. FAD 286A, the dextroenantiomer of the aromatase inhibitor fadrozole, might be a first candidate to investigate in humans, the physiological impact and therapeutic properties of aldosterone-synthase inhibition, especially in various forms of primary aldosteronism.

Use and side‐effect profile of spironolactone in a private cardiologist's practice

The beneficial effects of spironolactone on the treatment of cardiovascular diseases are well known, but translating these benefits into private practice can be difficult because of the drug's side-effect profile. When patients are monitored over the long term, spironolactone can be used safely with an acceptable side-effect profile. We retrospectively studied 762 patients taking spironolactone over a 7-year period in a cardiologist's referral-based practice and monitored them for side effects from the medication. Data were available on 762 patients. The average age of our patients when started on the medication was 67.2 +/- 0.5 years. Of these, 585 (76.8%) patients were treated for heart failure and 155 (20.3%) for hypertension. An average dose of 38.4 +/- 1.4 mg of spironolactone was used for treatment of all conditions. Of the 762 patients, 81 (10.6%) experienced side effects while using the medication; 40 had hyperkalemia (5.3%), 14 had gynecomastia (1.8%), and 15 had gastritis (2%). Of the patients with hyperkalemia, average creatinine clearance decreased from 64.6 +/- 5.8 ml/min at therapy start to 50.3 +/- 5.5 ml/min at the time of onset of side effects. Spironolactone can be used with an acceptable side-effect profile as long as patients are monitored long-term while receiving the medication.

Aldosterone Receptor Antagonists and Cardiovascular Disease: Do We Need a Change of the Guard?

Aldosterone is a mineralocorticoid primarily produced in the zona glomerulosa of the adrenal gland. For many years, aldosterone (Aldo) was thought to have its sole site of action in the kidney, where it regulated sodium excretion and potassium reabsorption. It is now known that Aldo is produced in cardiovascular tissues, and has been implicated in the development of ventricular hypertrophy and cardiac fibrosis. The precise mechanisms whereby Aldo acts in cardiac tissues are diverse. It was assumed that Aldo production could be limited by angiotensin-converting enzyme (ACE) inhibition, but serial measurements during therapy reveal only a transient decrease in Aldo levels. Moreover, the effects of Aldo on cardiac tissues occur even when angiotensin II (Ang II) has been suppressed or eliminated. Multiple investigators have examined effects of Aldo receptor blockade in human subjects and various animal models using the two Aldo receptor antagonists (ARAs), spironolactone and eplerenone. Major clinical trials involving spironolactone (RALES) and eplerenone (EPHESUS) ARAs have shown significant benefits in the treatment of congestive heart failure (CHF). In RALES, patients with New York Heart Association (NYHA) Class III or IV systolic heart failure treated with spironolactone had a 30% relative risk decrease in mortality. Although spironolactone is an effective competitive inhibitor of the mineralocorticoid receptor (MR), progestational and antiandrogenic side effects limit its use in some patients. Eplerenone, a more selective ARA, lacks these undesirable side effects. Although eplerenone is 20-fold less potent at the MR, it demonstrates efficacy similar to spironolactone, possibly due to decreased protein binding. Eplerenone has fewer side effects than spironolactone, which has been attributed to the low cross-reactivity with androgen and progesterone receptors. In EPHESUS, patients with left ventricular systolic dysfunction [Ejection Fraction (EF) <40%] and CHF following an acute myocardial infarction (AMI), were treated with eplerenone, resulting in a 17% reduction in cardiovascular mortality. However, these studies were limited in that diastolic function was not evaluated, although approximately 1/2 of CHF is due to diastolic dysfunction alone. To date, neither ARA has been studied for the treatment of diastolic dysfunction in a major clinical trial. However, numerous animal studies employing ARAs have shown a decrease in cardiac hypertrophy and fibrosis, indicating the potential benefits of these agents in the treatment of diastolic heart failure. In this review, we discuss possible underlying mechanisms responsible for Aldo effects on cardiovascular function and compare the beneficial effects of spironolactone and eplerenone in the treatment of heart disease.

Effects of aldosterone on cardiac local rennin- angiotensin -aldosterone system: an important role of cardiac fibroblasts

Recent studies showed cardiac local renin-angiotensin-aldosterone system (RAAS) play a pivotal role in pathophysiology in heart, and spironolactone, which is aldosterone blockade has beneficial effects on prognosis of patients with heart failure. We sought to determine how aldosterone, which is distal component of RAAS, acts on cardiac local RAAS using cultured cardiac myocytes and fibroblasts, and whether spironolactone inhibits these effects. Cultured cardiocytes were prepared from 1- or 2-day-old neonatal Sprague-Dawley rats by digestion with collagenase and pancratin. Cardiac myocytes and fibroblasts were separated by Percoll method and cultivated. After starvation period, aldosterone was added to culture medium and later, total RNA was extracted from the cells. mRNAs of renin, angiotensiongen, and ACE were semiquantified by RT-PCR. Basal mRNA expressions of renin, angiotensinogen, and ACE were observed in both cadiac myocytes and fibroblasts. After 48 hours of aldosterone stimulation, ACE mRNA was significantly upregulated in cardiac fibroblasts, however, gene expressions of renin and angiotensinogen were unchanged in cardiac fibroblasts and none of these RAAS component was upregulated in cardiac myocytes. Moreover, spironolactone completely inhibited aldosterone-induced augmentation of ACE gene expression in cardiac fibroblasts.In conclusion, our data support an idea that cardiac local RAAS has positive feedback system, which mainly depends on cardiac fibroblasts, and clinical beneficial effects of spironolactone may be partly due to blockage of positive feedback circuit.

Aldosterone and aldosterone antagonism in systemic hypertension.

Aldosterone mediates both water and electrolyte balance by acting on the renal mineralocorticoid receptors. Recent experimental studies have also documented the presence of these receptors in other body organs, including the brain, blood vessels, and heart, suggesting that aldosterone plays a larger role in normal physiologic function and in cardiovascular diseases such as systemic hypertension and congestive heart failure (CHF). The nonspecific aldosterone inhibitor spironolactone, and the selective aldosterone inhibitor eplerenone, are both approved for clinical use in treating patients with hypertension and/or symptomatic CHF. Studies have shown that spironolactone lowers blood pressure, improves endothelial function, reduces myocardial hypertrophy and fibrosis, and lowers the incidence of fatal arrhythmias. Eplerenone, which is more specific for the mineralocorticoid receptor, appears to provide all the beneficial effects of spironolactone in hypertensive patients, with the potential to modify many of the side effects related to nonspecific steroid-receptor blockade. Hyperkalemia remains a potential problem with all aldosterone antagonists.

Beneficial effects of spironolactone are independent of baseline aldosterone levels in severe congestive heart failure: results from the RALES neurohormonal substudy

Beneficial effects of spironolactone are independent of baseline aldosterone levels in severe congestive heart failure: results from the RALES neurohormonal substudy

Aldosterone receptor blockade in the management of heart failure.

Mounting evidence suggests that increased circulating aldosterone levels, despite angiotensin-converting-enzyme inhibitors therapy, may exert deleterious cardiovascular effects in heart failure, leading to clinical deterioration and poor prognosis. In the past decades, a number of experimental investigations have provided major insight into the mechanism(s) of action and the biological effects of aldosterone on the cardiovascular system, indicating that aldosterone participates in the structural and functional remodeling of cardiac and vascular tissue. In particular, it has emerged that aldosterone plays a key role in the regulation of myocardial extracellular matrix composition and endothelial function with important pathophysiological implications. Such evidence, coupled with the recent beneficial effects of spironolactone, a competitive aldosterone receptor antagonist, in reducing cardiac mortality and morbidity in patients with severe chronic heart failure treated with angiotensin-converting-enzyme inhibitors and loop diuretics, highlights the importance of aldosterone in the pathophysiology of human heart failure. The purpose of this review is to provide an overview of the regulation of aldosterone production and metabolism in heart failure, the basic mechanism of aldosterone action, and the pathophysiological implications of aldosterone in heart failure, and to discuss recent evidence supporting the efficacy of aldosterone receptor blockade in the treatment of chronic heart failure in humans.

Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: an analysis of 25 cases

Purpose: The beneficial effects of spironolactone are additive to those of ACE inhibitors among patients with heart failure and/or hypertension; however, it is essential to identify patients prone to develop serious hyperkalemia during combined treatment and to evaluate the associated morbidity and mortality. Subjects and methods: We studied 25 patients treated with ACE inhibitors and spironolactone who were admitted to the emergency room with a serum potassium level >6 mmol/L. Patients were followed up for at least one month after admission. Results: The mean age of the patients (11 males, 14 females) was 74 ± 13 years. Five patients were diabetics. On admission, the serum potassium was 7.7 ± 0.7 mmol/L and the serum creatinine was 3.8 ± 1.8 mg/dL; these values were significantly higher than the most recent follow-up laboratory measurements (4.6 ± 0.5 mmol/L and 1.9 ± 1.2 mg/dL, respectively) obtained at 13 ± 5 weeks before admission. The arterial pH on admission was 7.3 ± 0.1 and the plasma bicarbonate was 18 ± 5 mmol/L. The main causes for acute renal failure were dehydration (n = 12) and worsening heart failure (n = 9). The mean daily dose of spironolactone was 57 ± 32 mg and 12 patients were concomitantly treated with other drugs that may cause hyperkalemia. Two patients died, and 2 patients were resuscitated but survived. Hemodialysis was necessary in 17 patients; 12 patients were admitted to the intensive care unit. The mean duration of hospitalization was 12 ± 6 days. Two patients needed to be started on maintenance hemodialysis therapy. Conclusion: A combination of ACE inhibitors and spironolactone should be considered with caution and monitored closely in patients with renal insufficiency, diabetes, older age, worsening heart failure, a risk for dehydration, and in combination with other medications that may cause hyperkalemia. A daily spironolactone dose of 25 mg should not be exceeded.

Potential beneficial effects of spironolactone in CHF

Potential beneficial effects of spironolactone in CHF