Information

Spironolactone's role with adrenergic agents in heart failure?


I am studying the treatment plan of adrenergic agents for heart failure. Then, in the group discussion, spironolactone was included. But I cannot understand how it is relevant when considering adrenergic agents for treatment of heart failure. It is probably that it was only mentioned because adrenergic agents are usually used in combination with ABC therapy (antiplatelet, beta blockers,… ). This includes also diuretics.

Spironolactone is diuretic and antihypertensive. But I cannot understand how one can classify it adrenergic.

What is the role of spironolactone with adrenergic agents in heart failure?


Spironolactone works through a mechanism different than the adrenergics.

You said of the ABC approach, "This includes also diuretics." That's why Spironolactone was included.

Spironolactone is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents which act more proximally in the renal tubule. Aldosterone interacts with a cytoplasmic mineralocorticoid receptor to enhance the expression of the Na+, K+-ATPase and the Na+ channel involved in a Na+ K+ transport in the distal tubule . Spironolactone bind to this mineralcorticoid receptor, blocking the actions of aldosterone on gene expression. Aldosterone is a hormone; its primary function is to retain sodium and excrete potassium in the kidneys.

The lack of a decrease in the neuroendocrine prognostic markers, norepinephrine and endothelin-1, suggests that the beneficial effects of spironolactone are mainly related to mechanisms independent of the adrenergic and endothelin systems. The escape of AII and aldosterone, probably reflecting activated feedback mechanisms, confirms the specific activity of spironolactone on the renin-angiotensin-aldosterone system and supports the hypothesis that the beneficial effects of spironolactone on the progression of heart failure are mediated by the blockade of aldosterone receptors.

PubChem
Beneficial neurohormonal profile of spironolactone in severe congestive heart failure: Results from the RALES neurohormonal substudy


Therapeutic targets for heart failure: beyond beta-adrenergic and renin-angiotensin system blockade

Heart failure is a major healthcare problem and leading cause of death in Western countries. Growing evidence has shown recent improvements in pharmacological therapy, such as receptor-regulating agents, in treating heart failure however, the morbidity and mortality of heart failure is still high. More recent studies have suggested the presence of additional molecular targets for treating heart failure. Several key molecules in the beta adrenergic receptor signaling pathway play an important role in the progression of heart failure, and transgenic mice studies supported beneficial effects of controlling such molecules in heart failure. In addition, molecules in the renin-angiotensin system or calcium signaling pathway may also be potential targets for treating heart failure. In this review, we focused on putative mechanisms underlying the beneficial effects of regulating these molecules on the progression of heart failure including relevant patents on this topic.


The Control of Adrenergic Function in Heart Failure: Therapeutic Intervention

Chronic heart failure is characterised by excess adrenergic activity that augurs a poor prognosis. The reasons for increased adrenergic activity are complex and incompletely understood. The circumstantial evidence relating increased activity to adverse outcome is powerful, but not yet conclusive.

In normal subjects, autonomic control of the circulation is predominantly under the control of sympatho-inhibitory inputs from the arterial and cardiopulmonary baroreceptors, with a small input from the excitatory ergo- and chemo-receptors. In heart failure, the situation is reversed, with loss of the restraining input from the baroreceptors and an increase in the excitatory inputs, resulting in excessive adrenergic activity.

The circumstantial evidence linking neuroendocrine activation with poor outcome coupled with the clinical success of inhibition of the renin-angiotensin-aldosterone system has long suggested that inhibition of adrenergic activity might be beneficial in heart failure. There is a number of potential ways of achieving this. Improved treatment of heart failure itself may reduce sympathetic drive. There is an interplay between angiotensin II, aldosterone and the sympathetic nervous system, and thus RAAS antagonists, such as angiotensin converting enzyme inhibitors and spironolactone could directly reduce sympathetic activation. Exercise rehabilitation may similarly reduce sympathetic activity.

Recently, β-adrenergic receptor antagonists have been conclusively shown to improve symptoms, reduce hospitalisations and increase survival. However, the demonstration that central reduction of sympathetic activity with agents such as moxonidine increases morbidity and mortality suggests that we do not properly understand the role of sympathetic activation in the pathophysiology of heart failure.


What is the optimal medical management of ischaemic heart failure?

Ischaemic heart disease is probably the most important cause of heart failure. All patients with heart failure may benefit from treatment designed to retard progressive ventricular dysfunction and arrhythmias. Patients with heart failure due to ischaemic heart disease may also, theoretically, benefit from treatments designed to relieve ischaemia and prevent coronary occlusion and from revascularisation. However, there is little evidence to show that effective treatments, such as angiotensin converting enzyme (ACE) inhibitors and beta-blockers, exert different effects in patients with heart failure with or without coronary disease. Moreover, there is no evidence that treatment directed specifically at myocardial ischaemia, whether or not symptomatic, or coronary disease alters outcome in patients with heart failure. Some agents, such as aspirin, designed to reduce the risk of coronary occlusion appear ineffective or harmful in patients with heart failure. There is no evidence, yet, that revascularisation improves prognosis in patients with heart failure, even in patients who are demonstrated to have extensive myocardial hibernation. On current evidence, revascularisation should be reserved for the relief of angina. Large-scale, randomised controlled trials are currently underway investigating the role of specific treatments targeted at coronary syndromes in patients who have heart failure. The CHRISTMAS study is investigating the effects of carvedilol in a large cohort of patients with and without hibernating myocardium. The WATCH study is comparing the efficacy of aspirin, clopidogrel and warfarin. The HEART-UK study is assessing the effect of revascularisation on mortality in patients with heart failure and myocardial hibernation. Smaller scale studies are currently assessing the safety and efficacy of statin therapy in patients with heart failure. Only when the results of these and other studies are known will it be possible to come to firm conclusions about whether patients with heart failure and coronary disease should be treated differently from other patients with heart failure due to left ventricular systolic dysfunction.


Contents

Spironolactone is used primarily to treat heart failure, edematous conditions such as nephrotic syndrome or ascites in people with liver disease, essential hypertension, low blood levels of potassium, secondary hyperaldosteronism (such as occurs with liver cirrhosis), and Conn's syndrome (primary hyperaldosteronism). The most common use of spironolactone is in the treatment of heart failure. [26] On its own, spironolactone is only a weak diuretic because it primarily targets the distal nephron (collecting tubule), where only small amounts of sodium are reabsorbed, but it can be combined with other diuretics to increase efficacy. The classification of spironolactone as a "potassium-sparing diuretic" has been described as obsolete. [27] Spironolactone is also used to treat Bartter's syndrome due to its ability to raise potassium levels. [28]

Spironolactone has antiandrogenic activity. For this reason, it is frequently used to treat a variety of dermatological conditions in which androgens play a role. Some of these uses include acne, seborrhea, hirsutism, and pattern hair loss in women. [29] Spironolactone is the most commonly used medication in the treatment of hirsutism in the United States. [30] High doses of spironolactone, which are needed for considerable antiandrogenic effects, are not recommended for men due to the high risk of feminization and other side effects. Spironolactone is also commonly used to treat symptoms of hyperandrogenism, such as due to polycystic ovary syndrome, in women. [31]

Heart failure Edit

While loop diuretics remain first-line for most people with heart failure, spironolactone has shown to reduce both morbidity and mortality in numerous studies and remains an important agent for treating fluid retention, edema, and symptoms of heart failure. Current recommendations from the American Heart Association are to use spironolactone in patients with NYHA Class II-IV heart failure who have a left ventricular ejection fraction of less than 35%. [32]

In a randomized evaluation which studied people with severe congestive heart failure, people treated with spironolactone were found to have a relative risk of death of 0.70 or an overall 30% relative risk reduction compared to the placebo group, indicating a significant death and morbidity benefit of the medication. People in the study's intervention arm also had fewer symptoms of heart failure and were hospitalized less frequently. [33] Likewise, it has shown benefit for and is recommended in patients who recently suffered a heart attack and have an ejection fraction less than 40%, who develop symptoms consistent with heart failure, or have a history of diabetes mellitus. Spironolactone should be considered a good add-on agent, particularly in those patients "not" yet optimized on ACE inhibitors and beta-blockers. [32] Of note, a recent randomized, double-blinded study of spironolactone in patients with symptomatic heart failure with "preserved" ejection fraction (i.e. >45%) found no reduction in death from cardiovascular events, aborted cardiac arrest, or hospitalizations when spironolactone was compared to placebo. [34]

It is recommended that alternatives to spironolactone be considered if serum creatinine is greater than 2.5 mg/dL (221 μmol/L) in males or greater than 2 mg/dL (176.8 μmol/L) in females, if glomerular filtration rate is below 30 mL/min or with a serum potassium of greater than 5.0 mEq/L given the potential for adverse events detailed elsewhere in this article. Doses should be adjusted according to the degree of kidney function as well. [32]

According to a systematic review, in heart failure with preserved ejection fraction, treatment with spironolactone did not improve patient outcomes. This is based on the TOPCAT Trial examining this issue, which found that of those treated with placebo had a 20.4% incidence of negative outcome vs 18.6% incidence of negative outcome with spironolactone. However, because the p-value of the study was 0.14, and the unadjusted hazard ratio was 0.89 with a 95% confidence interval of 0.77 to 1.04, it is determined the finding had no statistical significance. Hence the finding that patient outcomes are not improved with use of spironolactone. [35] More recently, when blood samples from 366 patients in the TOPCAT study were analyzed for presence of canrenone (an active metabolite of spironolactone), 30% of blood samples from Russia lacked detectable residues of canrenone. This led to the conclusion that the TOPCAT trial results in Russia do not reflect actual clinical experience with spironolactone in patients with preserved ejection fraction. [36] The TOPCAT study results are now considered to have been invalidated. The study's prime investigator and other prominent research cardiologists are now advising physicians treating heart failure with preserved ejection fraction to consider prescribing spironolactone pending outcome of two multicenter trials of newer medications. [37]

Due to its antiandrogenic properties, spironolactone can cause effects associated with low androgen levels and hypogonadism in males. For this reason, men are typically not prescribed spironolactone for any longer than a short period of time, e.g., for an acute exacerbation of heart failure. A newer medication, eplerenone, has been approved by the U.S. Food and Drug Administration for the treatment of heart failure, and lacks the antiandrogenic effects of spironolactone. As such, it is far more suitable for men for whom long-term medication is being chosen. However, eplerenone may not be as effective as spironolactone or the related medication canrenone in reducing mortality from heart failure. [38]

The clinical benefits of spironolactone as a diuretic are typically not seen until 2–3 days after dosing begins. Likewise, the maximal antihypertensive effect may not be seen for 2–3 weeks. [ medical citation needed ]

Unlike with some other diuretics, potassium supplementation should not be administered while taking spironolactone, as this may cause dangerous elevations in serum potassium levels resulting in hyperkalemia and potentially deadly abnormal heart rhythms. [ medical citation needed ]

High blood pressure Edit

About 1 in 100 people with hypertension have elevated levels of aldosterone in these people, the antihypertensive effect of spironolactone may exceed that of complex combined regimens of other antihypertensives since it targets the primary cause of the elevated blood pressure. However, a Cochrane review found adverse effects at high doses and little effect on blood pressure at low doses in the majority of people with high blood pressure. [39] There is no evidence of person-oriented outcome at any dose in this group. [39]

Skin and hair conditions Edit

Androgens like testosterone and DHT play a critical role in the pathogenesis of a number of dermatological conditions including oily skin, acne, seborrhea, hirsutism (excessive facial/body hair growth in women), and male pattern hair loss (androgenic alopecia). [40] [41] In demonstration of this, women with complete androgen insensitivity syndrome (CAIS) do not produce sebum or develop acne and have little to no body, pubic, or axillary hair. [42] [43] Moreover, men with congenital 5α-reductase type II deficiency, 5α-reductase being an enzyme that greatly potentiates the androgenic effects of testosterone in the skin, have little to no acne, scanty facial hair, reduced body hair, and reportedly no incidence of male-pattern hair loss. [44] [45] [46] [47] [48] Conversely, hyperandrogenism in women, for instance due to polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (CAH), is commonly associated with acne and hirsutism as well as virilization (masculinization) in general. [40] In accordance with the preceding, antiandrogens are highly effective in the treatment of the aforementioned androgen-dependent skin and hair conditions. [49] [50]

Because of the antiandrogenic activity of spironolactone, it can be quite effective in treating acne in women. [51] In addition, spironolactone reduces oil that is naturally produced in the skin and can be used to treat oily skin. [52] [53] [41] Though not the primary intended purpose of the medication, the ability of spironolactone to be helpful with problematic skin and acne conditions was discovered to be one of the beneficial side effects and has been quite successful. [52] [53] Oftentimes, for women treating acne, spironolactone is prescribed and paired with a birth control pill. [52] [53] Positive results in the pairing of these two medications have been observed, although these results may not be seen for up to three months. [52] [53] Spironolactone has been reported to produce a 50 to 100% improvement in acne at sufficiently high doses. [54] Response to treatment generally requires 1 to 3 months in the case of acne and up to 6 months in the case of hirsutism. [54] Ongoing therapy is generally required to avoid relapse of symptoms. [54] Spironolactone is commonly used in the treatment of hirsutism in women, and is considered to be a first-line antiandrogen for this indication. [55] Spironolactone can be used in the treatment of female-pattern hair loss (pattern scalp hair loss in women). [56] There is tentative low quality evidence supporting its use for this indication. [57] Although apparently effective, not all cases of female-pattern hair loss are dependent on androgens. [58]

Antiandrogens like spironolactone are male-specific teratogens which can feminize male fetuses due to their antiandrogenic effects. [49] [59] [60] For this reason, it is recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception. [49] [59] [60] Oral contraceptives, which contain an estrogen and a progestin, are typically used for this purpose. [49] Moreover, oral contraceptives themselves are functional antiandrogens and are independently effective in the treatment of androgen-dependent skin and hair conditions, and hence can significantly augment the effectiveness of antiandrogens in the treatment of such conditions. [49] [61]

Spironolactone is not generally used in men for the treatment of androgen-dependent dermatological conditions because of its feminizing side effects, but it is effective for such indications in men similarly. [56] As an example, spironolactone has been reported to reduce symptoms of acne in males. [62] An additional example is the usefulness of spironolactone as an antiandrogen in transgender women. [63] [64] [65]

Topical spironolactone has been found to be effective in the treatment of acne as well. [66] As a result, topical pharmaceutical formulations containing 2% or 5% spironolactone cream became available in Italy for the treatment of acne and hirsutism in the early 1990s. [67] [68] The products were discontinued in 2006 when the creams were added to the list of doping substances with a decree of the Ministry of Health that year. [68]

Comparison Edit

Spironolactone, the 5α-reductase inhibitor finasteride, and the nonsteroidal antiandrogen flutamide all appear to have similar effectiveness in the treatment of hirsutism. [55] [69] [70] However, some clinical research has found that the effectiveness of spironolactone for hirsutism is greater than that of finasteride but is less than that of flutamide. [55] The combination of spironolactone with finasteride is more effective than either alone for hirsutism and the combination of spironolactone with a birth control pill is more effective than a birth control pill alone. [55] One study showed that spironolactone or the steroidal antiandrogen cyproterone acetate both in combination with a birth control pill had equivalent effectiveness for hirsutism. [55] Spironolactone is considered to be a first-line treatment for hirsutism, finasteride and the steroidal antiandrogen cyproterone acetate are considered to be second-line treatments, and flutamide is no longer recommended for hirsutism due to liver toxicity concerns. [55] The nonsteroidal antiandrogen bicalutamide is an alternative option to flutamide with improved safety. [71] [72]

The combination of spironolactone with a birth control pill in the treatment of acne appears to have similar effectiveness to a birth control pill alone and the combination of a birth control pill with cyproterone acetate, flutamide, or finasteride. [52] However, this was based on low- to very-low-quality evidence. [52] Spironolactone may be more effective than birth control pills in the treatment of acne, and the combination of spironolactone with a birth control pill may have greater effectiveness for acne than either alone. [73] In addition, some clinical research has found that flutamide is more effective than spironolactone in the treatment of acne. [52] In one study, flutamide decreased acne scores by 80% within 3 months, whereas spironolactone decreased symptoms by only 40% in the same time period. [74] [75] [76] However, the use of flutamide for acne is limited by its liver toxicity. [77] [78] [79] [80] Bicalutamide is a potential alternative to flutamide for acne as well. [81] [82] Spironolactone can be considered as a first-line treatment for acne in those who have failed other standard treatments such as topical therapies and under certain other circumstances, although this is controversial due to the side effects of spironolactone and its teratogenicity. [73] [50]

There is insufficient clinical evidence to compare the effectiveness of spironolactone with other antiandrogens for female-pattern hair loss. [83] The effectiveness of spironolactone in the treatment of both acne and hirsutism appears to be dose-dependent, with higher doses being more effective than lower doses. [73] [84] [85] However, higher doses also have greater side effects, such as menstrual irregularities. [52]

Transgender hormone therapy Edit

Spironolactone is frequently used as a component of feminizing hormone therapy in transgender women, especially in the United States (where cyproterone acetate is not available), usually in addition to an estrogen. [63] [64] [65] Other clinical effects include decreased male pattern body hair, the induction of breast development, feminization in general, and lack of spontaneous erections. [65] The medication is not approved for use as an antiandrogen by the Food and Drug Administration instead, it is used off-label for such purposes. [86]

Doses and forms Edit

Spironolactone is typically used at a low dosage of 25 to 50 mg/day in the treatment of heart failure, [87] [88] [89] [90] while it is used at low to high dosages of 25 to 200 mg/day in the treatment of essential hypertension, [87] [90] and at high dosages of 100 to 400 mg/day for hyperaldosteronism and ascites due to cirrhosis. [91] [92] [93] [94] The medication is typically used at high dosages of 100 to 200 mg/day in the treatment of skin and hair conditions in women, [95] [96] [97] [98] [99] and at high dosages of 100 to 400 mg/day in feminizing hormone therapy for transgender women. [100] [101] [102]

Spironolactone is available in the form of tablets (25 mg, 50 mg, 100 mg brand name Aldactone, others) and suspensions (25 mg/5 mL brand name CaroSpir) for use by mouth. [103] [104] [105] [106] [107] It has also been marketed in the form of 2% and 5% topical cream in Italy for the treatment of acne and hirsutism under the brand name Spiroderm, but this product is no longer available. [5] [108] The medication is also available in combination with other medications, such as hydrochlorothiazide (brand name Aldactazide, others). [107] [109] Spironolactone has poor water solubility, and for this reason, only oral and topical formulations have been developed other routes of administration such as intravenous injection are not used. [6] The only antimineralocorticoid that is available as a solution for parenteral use is the related medication potassium canrenoate. [110]

Contraindications of spironolactone include hyperkalemia (high potassium levels), severe and end-stage kidney disease (due to high hyperkalemia risk, except possibly in those on dialysis), Addison's disease (adrenal insufficiency and low aldosterone levels), and concomitant use of eplerenone. [111] [112] It should also be used with caution in people with some neurological disorders, no urine production, acute kidney injury, or significant impairment of kidney excretory function with risk of hyperkalemia. [111]

One of the most common side effects of spironolactone is frequent urination. Other general side effects include dehydration, hyponatremia (low sodium levels), mild hypotension (low blood pressure), [74] ataxia (muscle incoordination), drowsiness, dizziness, [74] dry skin, and rashes. Because of its antiandrogenic activity, spironolactone can, in men, cause breast tenderness, gynecomastia (breast development), feminization in general, and demasculinization, as well as sexual dysfunction including loss of libido and erectile dysfunction, although these side effects are usually confined to high doses of spironolactone. [113] At very high doses (400 mg/day), spironolactone has also been associated with testicular atrophy and reversibly reduced fertility, including semen abnormalities such as decreased sperm count and motility in men. [114] [115] However, such doses of spironolactone are rarely used clinically. [115] In women, spironolactone can cause menstrual irregularities, breast tenderness, and breast enlargement. [29] [52] [95] Aside from these adverse effects, the side effects of spironolactone in women taking high doses are minimal, and it is well tolerated. [52] [74] [116]

The most important potential side effect of spironolactone is hyperkalemia (high potassium levels), which, in severe cases, can be life-threatening. [111] Hyperkalemia in these people can present as a non anion-gap metabolic acidosis. [111] It has been reported that the addition of spironolactone to loop diuretics in patients with heart failure was associated with a higher risk of hyperkalemia and acute kidney injury (AKI). [117] Spironolactone may put people at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhea, cramping, and gastritis. [111] [118] In addition, there has been some evidence suggesting an association between use of the medication and bleeding from the stomach and duodenum, [111] though a causal relationship between the two has not been established. [119] Also, spironolactone is immunosuppressive in the treatment of sarcoidosis. [120]

Most of the side effects of spironolactone are dose-dependent. [51] Low-dose spironolactone is generally very well tolerated. [51] Even higher doses of spironolactone, such as 100 mg/day, are well tolerated in most individuals. [51] Dose-dependent side effects of spironolactone include menstrual irregularities, breast tenderness and enlargement, orthostatic hypotension, and hyperkalemia. [51] The side effects of spironolactone are usually mild and rarely result in discontinuation. [51]

High potassium levels Edit

Spironolactone can cause hyperkalemia, or high blood potassium levels. [115] Rarely, this can be fatal. [115] Of people with heart disease prescribed typical dosages of spironolactone, 10 to 15% develop some degree of hyperkalemia, and 6% develop severe hyperkalemia. [115] At a higher dosage, a rate of hyperkalemia of 24% has been observed. [121] An abrupt and major increase in the rate of hospitalization due to hyperkalemia from 0.2% to 11% and in the rate of death due to hyperkalemia from 0.3 per 1,000 to 2.0 per 1,000 between early 1994 and late 2001 has been attributed to a parallel rise in the number of prescriptions written for spironolactone upon the publication of the Randomized Aldactone Evaluation Study (RALES) in July 1999. [115] [121] [122] [26] However, another population-based study in Scotland failed to replicate these findings. [123] [124] The risk of hyperkalemia with spironolactone is greatest in the elderly, in people with renal impairment (e.g., due to chronic kidney disease or diabetic nephropathy), in people taking certain other medications (including ACE inhibitors, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs, and potassium supplements), and at higher dosages of spironolactone. [115] [26]

Although spironolactone poses an important risk of hyperkalemia in the elderly, in those with kidney or cardiovascular disease, and/or in those taking medications or supplements which increase circulating potassium levels, a large retrospective study found that the rate of hyperkalemia in young women without such characteristics who had been treated with high doses of spironolactone for dermatological conditions did not differ from that of controls. [52] [53] [125] This was the conclusion of a 2017 hybrid systematic review of studies of spironolactone for acne in women as well, which found that hyperkalemia was rare and was invariably mild and clinically insignificant. [52] These findings suggest that hyperkalemia may not be a significant risk in such individuals, and that routine monitoring of circulating potassium levels may be unnecessary in this population. [52] [53] [125] However, other sources have claimed that hyperkalemia can nonetheless also occur in people with more normal renal function and presumably without such risk factors. [26] Occasional testing on a case-by-case basis in those with known risk factors may be justified. [52] Side effects of spironolactone which may be indicative of hyperkalemia and if persistent could justify serum potassium testing include nausea, fatigue, and particularly muscle weakness. [52] Notably, non-use of routine potassium monitoring with spironolactone in young women would reduce costs associated with its use. [52]

Breast changes Edit

Spironolactone frequently causes breast pain and breast enlargement in women. [99] [126] This is "probably because of estrogenic effects on target tissue." [115] At low doses, breast tenderness has been reported in only 5% of women, but at high doses, it has been reported in up to 40% of women. [127] [51] Breast enlargement may occur in 26% of women at high doses and is described as mild. [74] Some women regard spironolactone-induced breast enlargement as a positive effect. [52]

Spironolactone also commonly and dose-dependently produces gynecomastia (breast development) as a side effect in men. [114] [126] [128] [129] At low doses, the rate is only 5 to 10%, [129] but at high doses, up to or exceeding 50% of men may develop gynecomastia. [114] [126] [128] In the RALES, 9.1% of men taking 25 mg/day spironolactone developed gynecomastia, compared to 1.3% of controls. [130] Conversely, in studies of healthy men given high-dose spironolactone, gynecomastia occurred in 3 of 10 (30%) at 100 mg/day, in 5 of 8 (62.5%) at 200 mg/day, and in 6 of 9 (66.7%) at 400 mg/day, relative to none of 12 controls. [131] [132] The severity of gynecomastia with spironolactone varies considerably, but is usually mild. [114] As with breast enlargement caused by spironolactone in women, gynecomastia due to spironolactone in men is often although inconsistently accompanied by breast tenderness. [114] In the RALES, only 1.7% of men developed breast pain, relative to 0.1% of controls. [130]

The time to onset of spironolactone-induced gynecomastia has been found to be 27 ± 20 months at low doses and 9 ± 12 months at high doses. [130] Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the medication. [114] However, after a sufficient duration of gynecomastia being present (e.g., one year), hyalinization and fibrosis of the tissue occurs and drug-induced gynecomastia may become irreversible. [133] [134]

Menstrual disturbances Edit

Spironolactone at higher doses can cause menstrual irregularities as a side effect in women. [51] These irregularities include metrorrhagia (intermenstrual bleeding), amenorrhea (absence of menstruation), and breakthrough bleeding. [51] They are common during spironolactone therapy, with 10 to 50% of women experiencing them at moderate doses and almost all experiencing them at a high doses. [74] [115] For example, about 20% of women experienced menstrual irregularities with 50 to 100 mg/day spironolactone, whereas about 70% experienced menstrual irregularities at 200 mg/day. [51] Most women taking moderate doses of spironolactone develop amenorrhea, and normal menstruation usually returns within two months of discontinuation. [115] Spironolactone produces an irregular and anovulatory pattern of menstrual cycles. [74] It is also associated with metrorrhagia and menorrhagia (heavy menstrual bleeding) in large percentages of women, [99] as well as with polymenorrhea (short menstrual cycles). [135] [136] The medication reportedly has no birth control effect. [137]

It has been suggested that the weak progestogenic activity of spironolactone is responsible for these effects, although this has not been established and spironolactone has been shown to possess insignificant progestogenic and antiprogestogenic activity even at high dosages in women. [74] [138] [139] An alternative proposed cause is inhibition of 17α-hydroxylase and hence sex steroid metabolism by spironolactone and consequent changes in sex hormone levels. [114] Indeed, CYP17A1 genotype is associated with polymenorrhea. [140] Regardless of their mechanism, the menstrual disturbances associated with spironolactone can usually be controlled well by concomitant treatment with a birth control pill, due to the progestin component. [74] [141]

Mood changes Edit

Research is mixed on whether antimineralocorticoids like spironolactone have positive or negative effects on mood. [142] [143] [144] In any case, it is possible that spironolactone might have the capacity to increase the risk of depressive symptoms. [142] [143] [144] However, a 2017 hybrid systematic review found that the incidence of depression in women treated with spironolactone for acne was less than 1%. [52] Likewise, a 10-year observational study found that the incidence of depression in 196 transgender women taking high-dose spironolactone in combination with an estrogen was less than 1%. [145]

Rare reactions Edit

Aside from hyperkalemia, spironolactone may rarely cause adverse reactions such as anaphylaxis, kidney failure, [146] hepatitis (two reported cases, neither serious), [147] agranulocytosis, DRESS syndrome, Stevens–Johnson syndrome or toxic epidermal necrolysis. [148] [149] Five cases of breast cancer in patients who took spironolactone for prolonged periods of time have been reported. [115] [129]

Spironolactone bodies Edit

Long-term administration of spironolactone gives the histologic characteristic of "spironolactone bodies" in the adrenal cortex. Spironolactone bodies are eosinophilic, round, concentrically laminated cytoplasmic inclusions surrounded by clear halos in preparations stained with hematoxylin and eosin. [150]

Pregnancy and breastfeeding Edit

In the United States, spironolactone is considered pregnancy category C meaning that it is unclear if it is safe for use during pregnancy. [3] [4] It is able to cross the placenta. [99] Likewise, it has been found to be present in the breast milk of lactating mothers and, while the effects of spironolactone or its metabolites have not been extensively studied in breastfeeding infants, it is generally recommended that women also not take the medication while nursing. [111] However, only very small amounts of spironolactone and its metabolite canrenone enter breast milk, and the amount received by an infant during breastfeeding (<0.5% of the mother's dose) is considered to be insignificant. [151]

A study found that spironolactone was not associated with teratogenicity in the offspring of rats. [152] [153] [154] Because it is an antiandrogen, however, spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses. [152] [153] In accordance, a subsequent study found that partial feminization of the genitalia occurred in the male offspring of rats that received doses of spironolactone that were five times higher than those normally used in humans (200 mg/kg per day). [152] [154] Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100 mg/kg per day). [154]

In practice however, although experience is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans. [152] [153] [155] [156] Among 31 human newborns exposed to spironolactone in the first trimester, there were no signs of any specific birth defects. [156] A case report described a woman who was prescribed spironolactone during pregnancy with triplets and delivered all three (one boy and two girls) healthy there was no feminization in the boy. [156] In addition, spironolactone has been used at high doses to treat pregnant women with Bartter's syndrome, and none of the infants (three boys, two girls) showed toxicity, including feminization in the male infants. [151] [152] There are similar findings, albeit also limited, for another antiandrogen, cyproterone acetate (prominent genital defects in male rats, but no human abnormalities (including feminization of male fetuses) at both a low dose of 2 mg/day or high doses of 50 to 100 mg/day). [156] In any case, spironolactone is nonetheless not recommended during pregnancy due to theoretical concerns relating to feminization of males and also to potential alteration of fetal potassium levels. [152] [157]

A 2019 systematic review found insufficient evidence that spironolactone causes birth defects in humans. [158] However, there was also insufficient evidence to be certain that it does not. [158]

Spironolactone is relatively safe in acute overdose. [111] Symptoms following an acute overdose of spironolactone may include drowsiness, confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, and diarrhea. [111] In rare cases, hyponatremia, hyperkalemia, or hepatic coma may occur in individuals with severe liver disease. [111] However, these adverse reactions are unlikely in the event of an acute overdose. [111] Hyperkalemia can occur following an overdose of spironolactone, and this is especially so in people with decreased kidney function. [111] Spironolactone has been studied at extremely high oral doses of up to 2,400 mg per day in clinical trials. [110] [159] Its oral median lethal dose (LD50) is more than 1,000 mg/kg in mice, rats, and rabbits. [111]

There is no specific antidote for overdose of spironolactone. [111] Treatment may consist of induction of vomiting or stomach evacuation by gastric lavage. [111] The treatment of spironolactone overdose is supportive, with the purpose of maintaining hydration, electrolyte balance, and vital functions. [111] Spironolactone should be discontinued in people with impaired kidney function or hyperkalemia. [111]

Spironolactone often increases serum potassium levels and can cause hyperkalemia, a very serious condition. Therefore, it is recommended that people using this medication avoid potassium supplements and salt substitutes containing potassium. [160] Physicians must be careful to monitor potassium levels in both males and females who are taking spironolactone as a diuretic, especially during the first twelve months of use and whenever the dosage is increased. Doctors may also recommend that some patients may be advised to limit dietary consumption of potassium-rich foods. However, recent data suggests that both potassium monitoring and dietary restriction of potassium intake is unnecessary in healthy young women taking spironolactone for acne. [125] Spironolactone together with trimethoprim/sulfamethoxazole increases the likelihood of hyperkalemia, especially in the elderly. The trimethoprim portion acts to prevent potassium excretion in the distal tubule of the nephron. [161]

Spironolactone has been reported to induce the enzymes CYP3A4 and certain UDP-glucuronosyltransferases (UGTs), which can result in interactions with various medications. [12] [162] [163] However, it has also been reported that metabolites of spironolactone irreversibly inhibit CYP3A4. [164] In any case, spironolactone has been found to reduce the bioavailability of oral estradiol, which could be due to induction of estradiol metabolism via CYP3A4. [165] Spironolactone has also been found to inhibit UGT2B7. [166] Spironolactone can also have numerous other interactions, most commonly with other cardiac and blood pressure medications, for instance digoxin. [111]

Licorice, which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism, has been found to inhibit the antimineralocorticoid effects of spironolactone. [167] [168] [169] Moreover, the addition of licorice to spironolactone has been found to reduce the antimineralocorticoid side effects of spironolactone in women treated with it for hyperandrogenism, and licorice hence may be used to reduce these side effects in women treated with spironolactone as an antiandrogen who are bothered by them. [167] [168] On the opposite end of the spectrum, spironolactone is useful in reversing licorice-induced hypokalemia. [170] [171] Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to attenuate the diuresis and natriuresis induced by spironolactone, but, not to affect its antihypertensive effect. [28] [172]

Some research has suggested that spironolactone might be able to interfere with the effectiveness of antidepressant treatment. As the medication acts as an antimineralocorticoid, it is thought that it might be able to reduce the effectiveness of certain antidepressants by interfering with normalization of the hypothalamic–pituitary–adrenal axis and by increasing levels of glucocorticoids such as cortisol. [173] [174] However, other research contradicts this hypothesis and has suggested that spironolactone might actually produce antidepressant effects, for instance studies showing antidepressant-like effects of spironolactone in animals. [175]

Pharmacodynamics Edit

The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition, among other more minor activities. [110] [113] [131] Spironolactone is a prodrug, so most of its actions are actually mediated by its various active metabolites. [110] The major active forms of spironolactone are 7α-thiomethylspironolactone (7α-TMS) and canrenone (7α-desthioacetyl-δ 6 -spironolactone). [6] [110]

Spironolactone is a potent antimineralocorticoid. [6] That is, it is an antagonist of the mineralocorticoid receptor (MR), the biological target of mineralocorticoids like aldosterone and 11-deoxycorticosterone. [6] By blocking the MR, spironolactone inhibits the effects of mineralocorticoids in the body. [6] The antimineralocorticoid activity of spironolactone is responsible for its therapeutic efficacy in the treatment of edema, high blood pressure, heart failure, hyperaldosteronism, and ascites due to cirrhosis. [178] [179] It is also responsible for many of the side effects of spironolactone, such as urinary frequency, dehydration, hyponatremia, low blood pressure, fatigue, dizziness, metabolic acidosis, decreased kidney function, and its risk of hyperkalemia. [180] Due to the antimineralocorticoid activity of spironolactone, levels of aldosterone are significantly increased by the medication, probably reflecting an attempt of the body to maintain homeostasis. [49] [74]

Spironolactone is a moderate antiandrogen. [113] [138] [163] That is, it is an antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). [113] [138] [163] By blocking the AR, spironolactone inhibits the effects of androgens in the body. [113] [138] [163] The antiandrogenic activity of spironolactone is mainly responsible for its therapeutic efficacy in the treatment of androgen-dependent skin and hair conditions like acne, seborrhea, hirsutism, and pattern hair loss and hyperandrogenism in women, precocious puberty in boys with testotoxicosis, and as a component of feminizing hormone therapy for transgender women. [138] [165] [181] It is also primarily responsible for some of its side effects, like breast tenderness, gynecomastia, feminization, and demasculinization in men. [114] [181] Blockade of androgen signaling in the breast disinhibits the actions of estrogens in this tissue. [182] Although useful as an antiandrogen in women, who have low testosterone levels compared to men, [183] [184] spironolactone is described as having relatively weak antiandrogenic activity. [96] [181] [185] [186]

Spironolactone is a weak steroidogenesis inhibitor. [113] [131] [138] [187] That is, it inhibits steroidogenic enzymes, or enzymes involved in the production of steroid hormones. [113] [131] [138] [187] Spironolactone and/or its metabolites have been found in vitro to weakly inhibit a broad array of steroidogenic enzymes including cholesterol side-chain cleavage enzyme, 17α-hydroxylase, 17,20-lyase, 5α-reductase, 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, 21-hydroxylase, and aldosterone synthase (18-hydroxylase). [138] [187] [188] [189] However, although very high doses of spironolactone can considerably decrease steroid hormone levels in animals, spironolactone has shown mixed and inconsistent effects on steroid hormone levels in clinical studies, even at high clinical doses. [52] [113] [131] [138] [163] In any case, the levels of most steroid hormones, including testosterone and cortisol, are usually unchanged by spironolactone in humans, which may in part be related to compensatory upregulation of their synthesis. [113] [131] [190] The weak steroidogenesis inhibition of spironolactone might contribute to its antiandrogenic efficacy to some degree and may explain its side effect of menstrual irregularities in women. [113] [114] However, its androgen synthesis inhibition is probably clinically insignificant. [54]

Spironolactone has been found in some studies to increase levels of estradiol, an estrogen, although many other studies have found no changes in estradiol levels. [113] [131] The mechanism of how spironolactone increases estradiol levels is unclear, but it may involve inhibition of the inactivation of estradiol into estrone and enhancement of the peripheral conversion of testosterone into estradiol. [191] [192] It is notable that spironolactone has been found in vitro to act as a weak inhibitor of 17β-hydroxysteroid dehydrogenase 2, an enzyme that is involved in the conversion of estradiol into estrone. [193] [194] Increased levels of estradiol with spironolactone may be involved in its preservation of bone density and in its side effects such as breast tenderness, breast enlargement, and gynecomastia in women and men. [191] [195] [196]

In response to the antimineralocorticoid activity spironolactone, and in an attempt to maintain homeostasis, the body increases aldosterone production in the adrenal cortex. [197] [198] [199] Some studies have found that levels of cortisol, a glucocorticoid hormone that is also produced in the adrenal cortex, are increased as well. [198] [199] [200] However, other clinical studies have found no change in cortisol levels with spironolactone, [138] [201] [85] [202] and those that have found increases often have observed only small changes. [203] In accordance, spironolactone has not been associated with conventional glucocorticoid medication effects or side effects. [204] [205]

Other activities of spironolactone may include very weak interactions with the estrogen and progesterone receptors and agonism of the pregnane X receptor. [85] [206] These activities could contribute to the menstrual irregularities and breast side effects of spironolactone and to its drug interactions, respectively. [207] [208] [209]

Pharmacokinetics Edit

The pharmacokinetics of spironolactone have not been studied well, which is in part because it is an old medication that was developed in the 1950s. [132] Nonetheless, much has been elucidated about the pharmacokinetics of spironolactone over the decades. [210] [211] [212] [6] [213] [214] [215] [216]

Absorption Edit

The bioavailability of spironolactone when taken by mouth is 60 to 90%. [6] [7] [8] The bioavailability of spironolactone and its metabolites increases significantly (+22–95% increases in levels) when spironolactone is taken with food, although it is uncertain whether this further increases the therapeutic effects of the medication. [218] [219] [220] The increase in bioavailability is thought to be due to promotion of the gastric dissolution and absorption of spironolactone, as well as due to a decrease of the first-pass metabolism. [218] [221] [222] The relationship between a single dose of spironolactone and plasma levels of canrenone, a major active metabolite of spironolactone, has been found to be linear across a dose range of 25 to 200 mg spironolactone. [96] Steady-state concentrations of spironolactone are achieved within 8 to 10 days of treatment initiation. [177] [223]

Little or no systemic absorption has been observed with topical spironolactone. [224]

Distribution Edit

Spironolactone and its metabolite canrenone are highly plasma protein bound, with percentages of 88.0% and 99.2%, respectively. [6] [9] Spironolactone is bound equivalently to albumin and α1-acid glycoprotein, while canrenone is bound only to albumin. [6] [9] Spironolactone and its metabolite 7α-thiospironolactone show very low or negligible affinity for sex hormone-binding globulin (SHBG). [225] [226] In accordance, a study of high-dosage spironolactone treatment found no change in steroid binding capacity related to SHBG or to corticosteroid-binding globulin (CBG), suggesting that spironolactone does not displace steroid hormones from their carrier proteins. [227] This is in contradiction with widespread statements that spironolactone increases free estradiol levels by displacing estradiol from SHBG. [85] [228]

Spironolactone appears to cross the blood–brain barrier. [229] [230]

Metabolism Edit

Spironolactone is rapidly and extensively metabolized in the liver upon oral administration and has a very short terminal half-life of 1.4 hours. [6] [7] The major metabolites of spironolactone are 7α-thiomethylspironolactone (7α-TMS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (7α-desthioacetyl-δ 6 -spironolactone). [6] [7] [176] These metabolites have much longer elimination half-lives than spironolactone of 13.8 hours, 15.0 hours, and 16.5 hours, respectively, and are responsible for the therapeutic effects of the medication. [6] [7] As such, spironolactone is a prodrug. [232] The 7α-thiomethylated metabolites of spironolactone were not known for many years and it was originally thought that canrenone was the major active metabolite of the medication, but subsequent research identified 7α-TMS as the major metabolite. [6] [176] [177] Other known but more minor metabolites of spironolactone include 7α-thiospironolactone (7α-TS), which is an important intermediate to the major metabolites of spironolactone, [12] as well as the 7α-methyl ethyl ester of spironolactone and the 6β-hydroxy-7α-methyl ethyl ester of spironolactone. [10]

Spironolactone is hydrolyzed or deacetylated at the thioester of the C7α position into 7α-TS by carboxylesterases. [12] [233] Following formation of 7α-TS, it is S-oxygenated by flavin-containing monooxygenases to form an electrophilic sulfenic acid metabolite. [12] This metabolite is involved in the CYP450 inhibition of spironolactone, and also binds covalently to other proteins. [12] 7α-TS is also S-methylated into 7α-TMS, a transformation catalyzed by thiol S-methyltransferase. [12] Unlike the related medication eplerenone, spironolactone is said to not be metabolized by CYP3A4. [234] However, hepatic CYP3A4 is likely responsible for the 6β-hydroxylation of 7α-TMS into 6β-OH-7α-TMS. [13] [235] 7α-TMS may also be hydroxylated at the C3α and C3β positions. [14] Spironolactone is dethioacetylated into canrenone. [15] Finally, the C17 γ-lactone ring of spironolactone is hydrolyzed by the paraoxonase PON3. [16] [236] It was originally thought to be hydrolyzed by PON1, but this was due to contamination with PON3. [16]

Elimination Edit

The majority of spironolactone is eliminated by the kidneys, while minimal amounts are handled by biliary excretion. [237]

Spironolactone, also known as 7α-acetylthiospirolactone, is a steroidal 17α-spirolactone, or more simply a spirolactone. [110] It can most appropriately be conceptualized as a derivative of progesterone, [130] [238] [223] itself also a potent antimineralocorticoid, in which a hydroxyl group has been substituted at the C17α position (as in 17α-hydroxyprogesterone), the acetyl group at the C17β position has been cyclized with the C17α hydroxyl group to form a spiro 21-carboxylic acid γ-lactone ring, and an acetylthio group has been substituted in at the C7α position. [239] [240] [241] These structural modifications of progesterone confer increased oral bioavailability and potency, [242] potent antiandrogenic activity, and strongly reduced progestogenic activity. [243] The C7α substitution is likely responsible for or involved in the antiandrogenic activity of spironolactone, as 7α-thioprogesterone (SC-8365), unlike progesterone, [244] is an antiandrogen with similar affinity to the AR as that of spironolactone. [245] In addition, the C7α substitution appears to be responsible for the loss of progestogenic activity and good oral bioavailability of spironolactone, as SC-5233, the analogue of spironolactone without a C7α substitution, has potent progestogenic activity but very poor oral bioavailability similarly to progesterone. [244] [246] [247]

Names Edit

Spironolactone is also known by the following equivalent chemical names: [239] [240] [241]

  • 7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
  • 7α-Acetylthio-3-oxo-17α-pregn-4-ene-21,17β-carbolactone
  • 3-(3-Oxo-7α-acetylthio-17β-hydroxyandrost-4-en-17α-yl)propionic acid lactone
  • 7α-Acetylthio-17α-(2-carboxyethyl)androst-4-en-17β-ol-3-one γ-lactone
  • 7α-Acetylthio-17α-(2-carboxyethyl)testosterone γ-lactone

Analogues Edit

Spironolactone is closely related structurally to other clinically used spirolactones such as canrenone, potassium canrenoate, drospirenone, and eplerenone, as well as to the never-marketed spirolactones SC-5233 (6,7-dihydrocanrenone 7α-desthioacetylspironolactone), SC-8109 (19-nor-6,7-dihydrocanrenone), spiroxasone, prorenone (SC-23133), mexrenone (SC-25152, ZK-32055), dicirenone (SC-26304), spirorenone (ZK-35973), and mespirenone (ZK-94679). [110]

Synthesis Edit

Chemical syntheses of spironolactone and its analogues and derivatives have been described and reviewed. [248]

The natriuretic effects of progesterone were demonstrated in 1955, and the development of spironolactone as a synthetic antimineralocorticoid analogue of progesterone shortly followed this. [130] [238] [249] [250] Spironolactone was first synthesized in 1957, [20] [249] [250] was patented between 1958 and 1961, [251] [252] and was first marketed, as an antimineralocorticoid, in 1959. [253] [254] Gynecomastia was first reported with spironolactone in 1962, [110] [255] and the antiandrogenic activity of the medication was first described in 1969. [256] This shortly followed the discovery in 1967 that gynecomastia is an important and major side effect of AR antagonists. [257] [258] Spironolactone was first studied in the treatment of hirsutism in women in 1978. [259] [167] [260] [261] [262] It has since become the most widely used antiandrogen for dermatological indications in women in the United States. [106] [263] [264] [265] Spironolactone was first studied as an antiandrogen in transgender women in 1986, and has since become widely adopted for this purpose as well, particularly in the United States where cyproterone acetate is not available. [266] [267] [268]

Early oral spironolactone tablets showed poor absorption. [269] The formulation was eventually changed to a micronized formulation with particle sizes of less than 50 μg, which resulted in approximately 4-fold increased potency. [269] [270]

Generic names Edit

The English, French, and generic name of the medication is spironolactone and this is its INN , USAN , USP , BAN , DCF , and JAN . [108] [109] [239] [271] Its name is spironolactonum in Latin, spironolacton in German, espironolactona in Spanish and Portuguese, and spironolattone in Italian (which is also its DCIT ). [108] [109] [271]

Spironolactone is also known by its developmental code names SC-9420 and NSC-150339. [108] [109] [239]

Brand names Edit

Spironolactone is marketed under a large number of brand names throughout the world. [108] [109] The major brand name of spironolactone is Aldactone. [108] [109] Other important brand names include Aldactone-A, Berlactone, CaroSpir, Espironolactona, Espironolactona Genfar, Novo-Spiroton, Prilactone (veterinary), Spiractin, Spiridon, Spirix, Spiroctan, Spiroderm (discontinued), [5] Spirogamma, Spirohexal, Spirolon, Spirolone, Spiron, Spironolactone Actavis, Spironolactone Orion, Spironolactone Teva, Spirotone, Tempora (veterinary), Uractone, Uractonum, Verospiron, and Vivitar. [108] [109]

Spironolactone is also formulated in combination with a variety of other medications, including with hydrochlorothiazide as Aldactazide, with hydroflumethiazide as Aldactide, Lasilacton, Lasilactone, and Spiromide, with altizide as Aldactacine and Aldactazine, with furosemide as Fruselac, with benazepril as Cardalis (veterinary), with metolazone as Metolactone, with bendroflumethiazide as Sali-Aldopur, and with torasemide as Dytor Plus, Torlactone, and Zator Plus. [109]

Availability Edit

Spironolactone is marketed widely throughout the world and is available in almost every country, including in the United States, Canada, the United Kingdom, other European countries, Australia, New Zealand, South Africa, Central and South America, and East and Southeast Asia. [108] [109]

Usage Edit

There was a total of 17.2 million prescriptions for spironolactone in the United States between the beginning of 2003 and the end of 2005. [272] There was a total of 12.0 million prescriptions for spironolactone in the United States in 2016 alone. [273] It was the 66th top prescribed medication in the United States in 2016. [273]

Prostate conditions Edit

Spironolactone has been studied at a high dosage in the treatment of benign prostatic hyperplasia (BPH enlarged prostate). [274] [275] [276] It was found to be better than placebo in terms of symptom relief following three months of treatment. [274] [275] However, this was not maintained after six months of treatment, by which point the improvements had largely disappeared. [274] [275] [276] Moreover, no difference was observed between spironolactone and placebo with regard to volume of residual urine or prostate size. [274] [275] Gynecomastia was observed in about 5% of people. [275] On the basis of these results, it has been said that spironolactone has no place in the treatment of BPH. [275]

Spironolactone has been studied and used limitedly in the treatment of prostate cancer. [277] [278] [28]

Epstein–Barr virus Edit

Spironolactone has been found to block Epstein–Barr virus (EBV) production and that of other human herpesviruses by inhibiting the function of an EBV protein SM, which is essential for infectious virus production. [279] This effect of spironolactone was determined to be independent of its antimineralocorticoid actions. [279] Thus, spironolactone or compounds based on it have the potential to yield novel antiviral medications with a distinct mechanism of action and limited toxicity. [279]

Other conditions Edit

Spironolactone has been studied in the treatment of rosacea in both males and females. [280] [281] [282] [62] [283]

Spironolactone has been studied in fibromyalgia in women. [284] [285] It has also been studied in bulimia nervosa in women, but was not found to be effective. [286]


The interplay of obesity and beta2-adrenergic receptors

Mineralocorticoid receptor antagonists interfere with the actions of aldosterone, but they do not inhibit the other principal mechanism of increased renal tubular sodium reabsorption in obese patients—the activation of renal sympathetic nerves (Figure 2). 4, 8 The secretion of leptin by adipocytes enhances sympathetic nerve traffic into the kidneys, where (via beta2-adrenergic receptors) it mediates an increase in sodium reabsorption (through a glucocorticoid receptor-mediated mechanism) by augmenting the activity of the Na + -Cl - co-transporter. 8, 23, 24 This pathway may explain why combined beta1- and beta2-adrenergic blockade may have greater natriuretic effects that antiadrenergic strategies that do not fully antagonize beta2-receptors 25 and why beta1-selective blockers have limited efficacy in patients with HFpEF. 26 It also suggests an advantage for spironolactone, which antagonizes glucocorticoid receptors more effectively than eplerenone. 27

Additionally, there is an intriguing interplay between beta2-adrenergic receptors, mineralocorticoid receptor signalling, leptin and obesity (Figure 2). The beta2-receptor gene is a susceptibility locus for hypertension, and certain polymorphisms are associated with salt sensitivity. 28, 29 Beta2-receptor stimulation enhances renal tubular sodium reabsorption, both directly and indirectly by facilitating the adrenal secretion of aldosterone 24, 28 in turn, both mineralocorticoid and glucocorticoid receptor signalling augments responsiveness to beta2-adrenergic agonists. 30, 31 In parallel, certain beta2-receptor polymorphisms are associated with the development of obesity and increased levels of leptin, 32-35 but have a blunted response to leptin-mediated sympathoexcitation. 36 Certain effects of leptin may be mediated through beta2-receptors, 37, 38 which can promote lipolysis and in turn suppress the expression of leptin, 39-42 although this negative feedback loop may be attenuated in obesity. 43 Furthermore, even though beta2-receptor stimulation may impair the clearance of natriuretic peptides in certain cells, 44 the clearance of these peptides by adipocytes is augmented by the hyperinsulinaemia that is commonly seen in ObHFpEF, 45 further potentiating the obesity-related attenuation of their effects on sodium excretion and lipolysis. 46 Mineralocorticoid receptor signalling may suppress the expression of leptin in adipocytes. 47 The mutually reinforcing interplay of beta2-adrenergic receptors, aldosterone, leptin and adiposity may be critical to sustaining the volume overload of ObHFpEF (Figure 2).


The term “inotrope” is familiar and intimately connected with pharmaceuticals clinically used for treatment of low cardiac output with cardiogenic shock. Traditional inotropic agents exert their effect by modulating calcium signaling in the myocardium. Their use is associated with poor long-term outcomes. Newer molecules in development intend to break from calcium mediation and the associated detrimental long-term effects by targeting distinct mechanisms of action to improve cardiac performance. Thus, “inotropy” does not sufficiently describe the range of potential novel pharmaceutical products. To enhance communication around and evaluation of current, emerging, and potential therapies, this review proposes a novel nuanced and holistic framework to categorize pharmacological agents that improve myocardial performance based on 3 myocardial mechanisms: calcitropes, which alter intracellular calcium concentrations myotropes, which affect the molecular motor and scaffolding and mitotropes, which influence energetics. Novel chemical entities can easily be incorporated into this structure, distinguishing themselves based on their mechanisms and clinical outcomes.

Dr. Psotka has received consulting fees from Amgen, Cytokinetics, and Roivant. Dr. Gottlieb has received consulting fees from BMS and has received research funding from Amgen, Novartis, Pfizer, and BMS. Dr. Francis has received consulting fees from Amgen, Cytokinetics, and Capricor Therapeutics has served on the Data and Safety Monitoring Board for Merck and Novartis and has been a member of the Advisory Board for Cytokinetics, Amgen, and Bayer. Dr. Allen has received consulting fees from ACI, Boston Scientific, Cytokinetics, Duke Clinical Research Institute, Janssen, and Novartis and has received research funding from the Patient-Centered Outcomes Research Institute, National Institutes of Health, and American Heart Association. Dr. Teerlink has research contracts with Abbott, Amgen, Bayer, Boerhinger Ingelheim, Bristol-Myers Squibb, Cytokinetics, Medtronic, Stealth Health, and Novartis and has received funding from Abbott, Amgen, Bayer, Bristol-Myers Squibb, Novartis, and scPharma. Dr. Adams has received consulting fees from Amgen, Cytokinetics, Merck, Novartis, Relypsa, and Roche and has received research funding from Amgen, Boehringer Ingelheim, Duke Clinical Research Institute, Merck, Novartis, Bristol-Myers Squibb, Roche Diagnostics, and Otsuka. Dr. Rosano has received consulting fees from Amgen. Dr. Lancelotti has reported that he has no relationships relevant to the contents of this paper to disclose.

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Don’t go bananas over spironolactone and potassium

Spironolactone has recently been in the news due to apparently unfounded concerns that taking it could increase the chances of contracting pandemic coronavirus or suffering from more severe COVID-19, so this is a good time to examine one of the classic misconceptions about this medication: the potential risk of elevated levels of potassium.

While spironolactone is widely used as a part of transfeminine hormone therapy (particularly in areas such as the United States where the antiandrogen cyproterone acetate is not available) to inhibit the masculinizing action of testosterone in those who still have testes, this is not the purpose it was originally meant to serve. Instead, it’s one of a class of drugs known as potassium-sparing diuretics used to treat high blood pressure and congestive heart failure by promoting greater excretion of water through urination, reducing blood volume and therefore reducing blood pressure in this role, its antiandrogenic action is a side effect.

Because it is a diuretic, spironolactone is commonly accompanied by the irritating side effect of more frequent urination. And because it does not result in the loss of potassium through excretion in urine, it has the potential to produce dangerously high levels of potassium, known as hyperkalemia. However, the actual extent of that risk has been a source of confusion in trans communities for many years. One widely reblogged Tumblr post shared an image of trans adult performer Bailey Jay posing with a banana, accompanied by one user’s commentary asserting that consuming a banana could actually put trans women in life-threatening danger due to the effects of spironolactone. (I’m fairly certain that the focus on bananas as a rich source of potassium comes from a generation’s familiarity with the third entry in the ”Honey, I Shrunk the Kids” series, in which the potassium content of bananas is prominently highlighted.)

But how much of a risk do potassium-rich foods actually pose to those taking spironolactone? In populations not suffering from heart failure, it would appear there is not much of a risk at all – certainly not to the point of a healthy person needing to change their typical diet. Because of its antiandrogenic effect, spironolactone is also used as a treatment for acne in cisgender women. Plovanovich, Weng, & Mostaghimi (2015) examined the medical records of 974 cis women who were taking spironolactone for acne and the rate of occurrence of hyperkalemia among this group, comparing this to baseline rates of hyperkalemia among this population when not taking spironolactone. 0.72% of patients taking spironolactone experienced hyperkalemia, compared to a baseline rate of 0.76%. In this dataset, spanning 2000 to 2014, no actual adverse events resulting from elevated potassium levels were observed, “indicating that any mild hyperkalemia was clinically insignificant.” Moreover, after followup testing of those patients who did have elevated potassium levels, these values were now found to be normal, “suggesting that the original measurements were erroneous or that the mild hyperkalemia was transient and quickly self-resolved.” Among this population, the authors could not “identify any instances of persistent and clinically meaningful hyperkalemia in 14 years of clinical data”.

Layton et al. (2017), reviewing Plovanovich et al. and other studies, concluded that “routine potassium monitoring is largely unnecessary unless risk factors are present.” However, Thiede et al. (2019) did recommend potassium monitoring in cis women over the age of 45 taking spironolactone for acne, on the basis that hyperkalemia was observed in 1 of 112 women aged 18-45 and 2 of 12 women over 45. In terms of the transfeminine population specifically, Millington, Liu, & Chan (2019) reported that of 88 trans youth with a mean age of 16.6 years treated with spironolactone at Boston Children’s Hospital, only 2.2% of these youth experienced hyperkalemia, and all of these measurements returned to normal when potassium levels were taken again. Additionally, none of them experienced actual symptoms of hyperkalemia, and the researchers stated that “Routine electrolyte monitoring in this population in the absence of other medical comorbidities may be unnecessary.” Nevertheless, the Endocrine Society’s clinical guidelines for endocrine treatment of trans people (Hembree et al., 2017) recommend that “For individuals on spironolactone, serum electrolytes, particularly potassium, should be monitored every 3 mo in the first year and annually thereafter”. And the comprehensive metabolic panel (CMP), a typical component of regular blood tests for trans people on HRT, includes the measurement of potassium levels. Trans women and transfeminine people taking spironolactone are unlikely to experience hyperkalemia when they do, they typically do not experience symptoms of hyperkalemia or adverse events and routine blood tests this population already undergoes would detect hyperkalemia.

It’s also worth considering that a wide variety of foods that are commonplace in many diets contain an amount of potassium comparable to or greater than that of bananas. A trans woman eating a banana is taken as cause for concern – but nobody seems to bat an eye when we enjoy potatoes, spinach, avocados, sweet potatoes, butternut squash, black beans, tomato paste, or coconut water. Somehow, french fries just haven’t achieved the same notoriety in relation to trans women as bananas, but if bananas were truly worrisome, trans women on spironolactone would regularly be experiencing the effects of elevated potassium simply from eating many of the foods that most people consume regularly. Those trans people who express worry about the impact of eating a banana might well be ingesting copious quantities of potassium already without realizing it or noticing anything is amiss – because, most likely, nothing is.


Preferred beta-blockers for the treatment of heart failure

Carvedilol and nebivolol are the third generation beta blockers of choice for heart failure together with the second generation beta blockers bisoprolol and metoprolol succinate.

Introduction

Beta-adrenergic receptor blockers play an important role in the management of cardiovascular disease, including hypertension, ischemic heart disease and chronic heart failure. They differ, though, in beta-selectivity, vasodilation properties, and other ancillary features.

Recently, third generation, vasodilating, beta-blockers were introduced into practice.

  • Carvedilol is a non-selective beta-blocker with additional alpha1-blocking and antioxidant activities.
  • Nebivolol is a novel beta-blocker with both a greater degree of selectivity for beta-1 adrenergic receptors than other agents in this class and an ability to stimulate endothelial nitric oxide production, leading to vasodilation and other potential clinical effects.

I - CARVEDILOL

1) Mechanisms and clinical effects

Third generation beta blockers have distinctive vasodilator activity.

  1. The first example of this group, labetolol is non-selective.
  2. Carvedilol blocks the beta-1 receptors 2-3 times more than alpha-1 receptors.
  3. Bucindolol is a non-selective agent and blocks the alpha receptors as well.

The vasodialtor effect of these three agents is obtained via the blockade of the alpha receptors. However nebivolol shows a highly selective beta-1 blocking effects and confers an endothelium dependent vasodilatation via activation of L-arginin/NO pathway.

  • is a third generation lipophylic beta blocker with antioxydant properties which block both beta-1 and alpha-1 adrenergic receptors(1). Its affinity to beta-1 receptors is 2-3 times much higher than alpha-1 receptors.
  • has S and R enantiomeres and both have equal alpha blocking effects but S enantiomere shows stronger beta blockade (2).

After oral administration, absorption is fast and reaches maximum plasma concentration within 1-2 hours. The plasma half-life is 7-10 hours, and should be given twice daily. As it is metabolised mainly by the liver, the pharmacokinetics are changed in liver diseases.

Unlike traditional beta blockers carvedilol :

  • has a positive effect on renal hemodynamics.
  • increases renal blood flow and decreases microalbuminuria (3,4).
  • has a neutral effect on insulin resistance, triglyceride and cholesterol (5).

2) Clinical Trials

  • In the COMET trial (Carvedilol Or Metoprolol European Trial) the carvedilol group showed a lower probability of new diabetes development (6).
    The vasodilator effect of carvedilol increases the insulin dependent glucose influx into the myocytes and increases insulin sensitivity. Traditional beta blockers on the other hand may cause peripheral vasoconstriction and disturb the glucose utilisation in the periphery and reduces insulin sensitivity (7).

Its distinctive features allow different applications and usage and there are several trials for various conditions.

  • A Meta-analysis of 36 clinical trials which included 3412 patients showed that 25 mg carvedilol decreased systolic blood pressure by 9.6 % and diastolic blood pressure by 10.7 % (2). Unlike other beta blockers, carvedilol preserves the cardiac output and reduces the peripheral resistance in hypertensive patients.
  • The CAPRICORN study was designed to explore the beneficial effects of carvedilol in post myocardial infarction patients with depressed left ventricular function (EF< 40 %) . When added to standard treatment including ACE-inhibitors, the carvedilol groupe showed a 23 % reduction in all cause mortailty (8).
  • Apart from the two second generation beta blockers metoprolol and bisoprolol, carvedilol has also been shown to be effective in heart failure to reduce morbidity and mortality. The US Carvedilol study reported a 65 % mortality reduction in Class III or IV patients with heart failure when carvedilol added on usual care including digoxin, diuretics and ACE inhibitors (9).
  • However this particular study had a small number of Class IV patients and the COPERNICUS study was set up to investigate the effects of carvedilol in Class III and IV patients and revealed a 35 % reduction in all cause mortality (10).
  • The COMET trial&rsquos aim was to point out the differences between a second generation beta blocker metoprolol (tartrate) and a third generation beta blocker carvedilol in heart failure patients in nearly a five years follow-up.
    The study ended up with a 17 % reduction in total mortality by carvedilol and the difference was present in all the sub-groups except for women, probably due to the relatively small number of women in the study.
  • The results of COMET have been interpreted in different ways. The first possibility is the difference between the molecules. However some authors criticised using the metoprolol tartrate in relatively low dose to compare carvedilol as metoprolol succinate was shown to be effective in reducing mortality in the MERIT-HF trial (11).
  • Despite the fact that carvedilol distinctively blocks the rapidly depolarised sodium channels and L-type calcium channels there is no data to prove the difference in the antiarrhythmic efficacy of carvedilol as compared to the other beta blockers.

There is some evidence suggesting the preventive effects of carvedilol for nitrate tolerance (12).
Side effects include rare vertigo, tiredness and headache. Erectile dysfunction may also be a problem.

II - NEBIVOLOL

1) Mechanisms and clinical effects

  • a selective beta-1 adrenergic receptor blocker with nitric oxide dependent vasodilator and antioxidant effects.
    It is a mixture of D and L isomeres. D-nebivolol is a selective beta-1 antagonist while L-nebivolol is responsible for the nitric oxide dependent vasodilator effect.
  • Its negative inotropic effect is lower than metoprolol and carvedilol and does not have any membrane stabilising or intrinsic sympathomimetic effects. It is mainly metabolised by the liver (13-15). Clinical trials showed neutral effects on lipid and glucose metabolism.
  • causes a dose dependent nitric-oxide related renal artery dilatation and increases glomerular filtration rate, urine flow and sodium chloride excertion (16-17).

2) Clinical trials

  • Nebivolol as an antihypertensive agent was tested in 6376 patients in whom a significant reduction both in systolic and diastolic blood pressure has been achieved. Nebivolol was well tolerated and had neutral metabolic effects (18). The studies comparing nebivolol (5 mg) with losartan (50 mg), lisinopril (10-40 mg), amlodipin (5-10 mg) and nifedipin (20mg bid) showed no inferiority of nebivolol in terms of both systolic and diastolic blood pressure reduction(19).
  • Nitric oxide behaves as an endogenous inhibitor of platelet aggregation in the platelets and nebivolol inhibits platelet aggregation triggered by adenosine diphospate and collagen (20). It has also been shown Nebivolol inhibits proliferation of human coronary endothelial cells, aortic smooth muscle cells and smooth muscle cells via nitric oxide delivery (21).
  • Nebivolol has been tried extensively in patients with heart failure. In one study nebivolol has been demonstrated to reduce the heart rate and increase ejection fraction, decrease left ventricular end diastolic pressure, pulmonary capillary pressure and peripheral vascular resistance in patients with Class I-II heart failure patients with an ejection fraction lower than 24 % in a three months' follow-up (22). Nebivolol has also favorable effects on diastolic compliance (23).
  • The SENIORS study was designed to investigate the effects of nebivolol in the elderly (<70 years ) with heart failure with or without low ejection fraction in both genders The previous beta blockers in heart failure trials (US-Carvedilol and COPERNICUS with carvedilol, MERIT-HF with metoprolol and CIBIS II with bisoprolol) had not included elderly patients.

III &ndash Other Third Generation Beta-Blockers

Blocks the alpha-1, beta-1 and beta-2 receptors and alpha-1 receptor blokade is responsible for the vasodilator effect. It has a partial agonist effect and is metabolised mainly by the liver.

Bucindolol is a non-selective and lipophilic beta blocker with a higher affinity then beta receptors. Vasodilator effects seem to be due to direct alpha-1 blockade(2).

BEST (Beta-Blocker Evaluation of Survival Trial) failed to show any benefit of bucindolol for total mortality in Class III-IV heart failure patients when added to the usual care (25). In the Class IV patients bucindolol even increased the composite end point of death and heart failure hospitalisations in six-months follow-up. The annual mortality for Class IV patients in the placebo group of the BEST study was 28 % which was higher than CIBIS (20 %), COPERNICUS (19 %) and MERIT-HF (25 %) studies. It has been suggested that the Class IV patients in BEST study were much sicker than the other studies and this contributed to the less beneficial effect of bucindolol in the BEST study.

Celiprolol is a third generation beta blocker with a weak beta-2 agonist activity and weak alpha 2 blocker and direct smooth muscle relaxing properties. It reduces peripheral vascular resistance and has similar antihypertensive effects to metoprolol, propronalol, atenolol and pindolol. In a study on heart failure patients comparing metoprolol, placebo and celiprolol, both drugs were well tolerated but celiprolol did not show any additional benefit (26,27).

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

All beta blockers are not the same in their effects. Although it seems that their antihypertensive efficacy is a class effect, it may not be easy to consider their beneficial effects in heart failure as a class effect. Moreover their metabolic effects are also different, third generation beta blockers being more neutral or positive.

Carvedilol and nebivolol are the third generation beta blockers of choice for heart failure together with the second generation beta blockers bisoprolol and metoprolol succinate.

References

(1) Feuerstein GZ, Ruffolo RR Jr. Carvedilol, a novel multiple action antihypertensive agent with antioxidant activity and the potential for myocardial and vascular protection. Eur Heart J 199516(suppl F): 38-42.

(2) Dunn CJ, Lea AP, Wagstaff AJ. Carvedilol: a reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders. Drugs 199754:161-185.

(3) Agrawal B, Wolf K, Berger A, et al. Effect of antihypertensive treatment on qualitative estimates of microalbuminuria. J Hum Hypertens 199610:551-5.

(4) Abraham WT, Tsvetkova T, Lowes BD, et al. Carvedilol improves renal hemodynamics in patients with chronic heart failure [abstract]. Circulation 199898:I-378&ndashI-379.
(5) Jacop S, Rett K, Wicklmayr M, et al. Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study. J Hypertens 199614:489-494.

(6) Poole-Wilson PA, Swedberg K, Cleland JG, et al, for the Carvedilol Or Metoprolol European Trial Investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003362:7-13.

(7) Giugliano D, Acampora R, Marfella R, et al. Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin- dependent diabetes mellitus and hypertension: a randomized controlled trial. Ann Intern Med 1997126:955-959.

(8) Colucci WS. Landmark Study: The Carvedilol Post-Infarct Survival Control in left ventricular dysfunction study (CAPRICORN). Am J Cardiol 200493(suppl):13B-16B.

(9) Packer M, Bristow M, Cohn J, et al. The effect of carvedilol on mortality and morbidity in patients with chronic heart failure. N Engl J Med 1996334:1349-1355.

(10) Packer M, Coats AJS, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001344:1651-1658.

(11) MERIT-HF Investigators. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL Randomized Intervention Trial in Congestive Heart failure (MERIT-HF). Lancet 1999353:2001-2007.

(12) El-Demerdash E. Evidences for prevention of nitroglycerin tolerance by carvedilol. Pharmacological Research 200653:380-385.
(13) Troost R, Schwedhelm E, Rojczyk S et al. Nebivolol decreases systemic oxidative stress in healthy volunteers. British J Clin Pharmacol 200050:377-79.

(14) Fratta Pasini AF, Garbin U, Nava MC, et al. Nebivolol decreases oxidative stress in essential hypertensive patients and increases nitric oxide by reducing its oxidative inactivation. J Hypertens 200523(3):589-96

(15) Brixius K, Bundkirchen, Bolck B et al. Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium. Brit J Pharmacol 2001133:1330-8.

(16) Kakoki M, Hirata Y, Hayakawa H et al. Effects of vasodilatotory B-adrenoceptor antagonists on endothelium derived nitric oxide release in rat kidney. Hypertension 199933(part II):467-71.

(17) Greven J, Gabriels G. Effect of nebivolol, a novel B1-selective adrenoceptor antagonist with vasodilating properties, on kidney function. Arzneim Forsch/drug Res 200050:973-79.

(18) Fallois JV, Faulhaber H-D: Nebivolol, a beta-blocker of the third generation: the current treatment of arterial hypertension: results of a multicenter observational study. Praxis 200190:435-441.

(19) Weber MA. The Role of the new ?-blockers in treating cardiovascular disease. Am J Hypertens 200518169S-176S.

(20) Falciani M, Rinaldii B, D&rsquoAgostino B, et al. Effects of nebivolol on human platelet aggregation. J Cardiovasc Pharmacol 200138:922-29.

(21) Brehm BR, Wolf SC, Bertsch D, et al. Effects of nebivolol on proliferation and apoptosis of human coronary artery smooth muscle and endothelial cells. Cardiovasc Res 200149:430-9.

(22) Wisenbaugh T et al. Long-term (3 months) effect of new b-blocker (nebivolol) on cardiac performance in dilated cardiomyopathy. J Am Coll Cardiol 199321:1094-1100.

(23) Nodari S, Meta M, Dei Cas L. Beta blocker treatment of patients with diastolic heart failure and arterial hypertension. A prospective, randomized, comparison of the long-term effects of atenolol vs nebivolol. Eur J Heart Failure 20035:621-7.

(24) Flather MD, Shibata MC, Coats AJS, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascusar hospital admission in elderly patients with heart failure (SENIORS). European Heart J 200526:215-225.

(25) The Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001344:1659-67.
(26) Anderson JL, Krause-Steinrauf H, Goldman S, et al for the Beta-blocker Evaluation of Survival Trial (BEST) Investigators. Failure of benefit and early hazard of bucindolol for class IV heart failure. J of Cardiac Failure 20039:266-77.

(27) Sanderson JE, Chan SKW, Yu CM. ß-blockers in heart failure: a comparison of a vasodilating ß-blocker with metoprolol. Heart 199879:86-92.