Spironolactone is a mineralocorticoid (aldosterone) receptor antagonist (aldosterone antagonist) and a potassium-sparing diuretic.256,265
Spironolactone is used in the management of edema associated with excessive aldosterone excretion such as idiopathic edema and edema accompanying cirrhosis of the liver, nephrotic syndrome, and heart failure, usually in conjunction with other diuretics. Careful etiologic diagnosis should precede the use of any diuretic. Although thiazides and chlorthalidone are more rapidly acting and more effective diuretics, spironolactone does not cause potassium depletion as may result from thiazide or chlorthalidone therapy. In addition, spironolactone is a useful adjunct to thiazide therapy when diuresis is inadequate or reduction of potassium excretion is necessary. When used in conjunction with a thiazide diuretic in the treatment of edema associated with cirrhosis of the liver, spironolactone should be given for 2-3 days prior to administration of the thiazide diuretic in order to prevent potassium depletion and precipitation of hepatic coma.
Spironolactone is used in the management of hypertension, usually in conjunction with other diuretics or hypotensive agents. Used alone, spironolactone produces a modest lowering of blood pressure in most patients with hypertension, and blood pressure returns to within normal limits in about 20% of patients.
Because of established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes), current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics).501,502,503,504,1200 However, aldosterone antagonists (e.g., spironolactone, eplerenone) may be considered as add-on therapy if goal blood pressure cannot be achieved with the recommended drugs, and are considered preferred add-on therapy by some experts for resistant hypertension and for hypertension associated with primary aldosteronism.265,501,502,503,504,1200 Some experts also state that aldosterone antagonists such as spironolactone may be useful for the management of resistant hypertension in patients with type 2 diabetes mellitus when added to an existing treatment regimen consisting of a renin-angiotensin system inhibitor (e.g., ACE inhibitor, angiotensin II receptor antagonist), diuretic, and calcium-channel blocker.1215 However, therapy with an ACE inhibitor or angiotensin II receptor antagonist in conjunction with an aldosterone antagonist may increase the risk of hyperkalemia.1200,1215 Additionally, aldosterone antagonists may be particularly useful in selected patients with heart failure or following myocardial infarction (MI).524,527,700 For information on antihypertensive therapy for patients with heart failure or following MI, see Heart Failure and also see Ischemic Heart Disease under Hypertension in Adults: Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors, in Uses in the Thiazides General Statement 40:28.20.
Spironolactone may be useful to decrease the potassium loss caused by other diuretics and potentiate the hypotensive effects of those agents or other more potent hypotensive agents. In addition, the drug may be useful in hypertensive patients with gout or diabetes mellitus that may be aggravated by thiazide diuretics. Spironolactone should be avoided in patients with renal insufficiency and in those receiving potassium supplements or other potassium-sparing diuretics.1200
For additional information on the role of aldosterone antagonists in the management of hypertension in patients with underlying cardiovascular risk factors and information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.
Spironolactone is used in the management of severe heart failure (New York Heart Association [NYHA] functional class III-IV) in conjunction with standard therapy for heart failure to increase survival and reduce heart failure-related hospitalizations.265,524,700
Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure.524,700,701,703 Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations.524,700 For additional information on the management of heart failure, see Uses: Heart Failure, in Carvedilol 24:24, Enalaprilat/Enalapril 24:32.04, and Sacubitril and Valsartan 24:32.92. The American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) recommend the addition of an aldosterone antagonist (i.e., spironolactone or eplerenone) in selected patients with heart failure and reduced LVEF who are already receiving a β-blocker and an agent to inhibit the renin-angiotensin-aldosterone (RAA) system (e.g., ACE inhibitor, angiotensin II receptor antagonist, ARNI); careful patient selection is required to minimize the risk of hyperkalemia and renal insufficiency.524,700 (See Cautions: Electrolyte and Metabolic Effects.)
Aldosterone receptor antagonists are also recommended, unless contraindicated, in conjunction with other heart failure therapy to reduce morbidity and mortality following acute MI in patients with reduced LVEF who develop symptoms of heart failure or who have a history of diabetes mellitus.524 ACCF and AHA state that there are limited data to support or refute whether spironolactone and eplerenone are interchangeable.524 The perceived difference between eplerenone and spironolactone is attributed to the selectivity of aldosterone receptor antagonism and not the effectiveness of mineralocorticoid-blocking activity.524 (See Pharmacology.)
The concomitant use of spironolactone and an ACE inhibitor had been considered relatively contraindicated because of the potential for developing severe hyperkalemia.215,217,218,222 In addition, it was believed that ACE inhibitors would inhibit formation of aldosterone, a hormone associated with the pathophysiology of heart failure, by suppressing the RAA system.215,219,227,231 However, results of several studies have indicated that ACE inhibitors only transiently inhibit the production of aldosterone, and the addition of spironolactone to ACE inhibitor therapy may augment the suppressive effect of ACE inhibitors on aldosterone.215,218,219,246,251,252,253,254 (See Pharmacology: Cardiovascular Effects.)
Results of a randomized, multicenter, controlled study (Randomized Aldactone Evaluation Study [RALES]) in 1663 patients with moderate or severe heart failure (NYHA functional class III or IV) and LVEF of 35% or less indicate that addition of low-dose (25-50 mg daily) spironolactone to standard therapy (e.g., an ACE inhibitor and a loop diuretic with or without a cardiac glycoside was associated with decreases in overall mortality and hospitalization (for worsening heart failure) rates of approximately 30 and 35%, respectively, compared with standard therapy and placebo.215,218,246,247 The reduction in mortality and hospitalization rates was observed within 2-3 months of initiation of combined therapy and continued throughout the study (mean follow-up: 24 months).215,247 The combined therapy also was associated with an improvement in NYHA functional class in about 41% of patients.215 Because interim analysis of this study after a mean follow-up of 24 months revealed that morbidity and death were reduced significantly in patients receiving spironolactone concomitantly with standard therapy compared with those receiving standard therapy and placebo, the study was discontinued.215,246
Spironolactone also is used for the management of edema and sodium retention in patients with heart failure who do not respond adequately to or are intolerant of other therapeutic measures.265 (See Uses: Edema.)
Spironolactone is used for the short-term preoperative treatment of primary hyperaldosteronism and for long-term maintenance therapy in patients with discrete aldosterone-producing adrenal adenomas who are not candidates for surgery (e.g., adrenalectomy).265 The drug also is used for long-term maintenance therapy for patients with bilateral micronodular or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism).265
Spironolactone is used for its antiandrogenic effects in combination with testolactone in the management of certain forms of gonadotropin releasing hormone (GnRH)-independent (peripheral) precocious puberty (e.g., familial male precocious puberty [testotoxicosis]).203,204,205,206,207,208,211,213 Such therapy has effectively controlled acne, spontaneous erections, and aggressive behavior and slowed accelerated growth and skeletal maturation, at least in the short term (e.g., 2 years), in boys with familial precocious puberty.203,204,205,206 Neither drug alone effectively controls pubertal characteristics nor the rate of growth and skeletal maturation in boys with this condition,206 although some benefit (e.g., on height velocity) with testolactone alone may be apparent.206 Testolactone generally prevents the gynecomastia that may be associated with spironolactone.206 Testolactone also has been used in combination with other antiandrogens (e.g., flutamide) in the management of this condition, but experience is less extensive.206,213 While spironolactone currently is the most widely used antiandrogenic drug in familial male precocious puberty, alternative antiandrogenic drugs (e.g., flutamide) that avoid some of the potentially serious adverse effects of spironolactone therapy (e.g., mineralocorticoid-antagonist effects) are being studied for this condition and congenital adrenal hyperplasia.206,207,212 However, concerns about potential hepatotoxic effects of flutamide may limit the use of this drug in such precocious puberty.213 A gradual escape from the beneficial effects of combined therapy with spironolactone and testolactone may occur during long-term therapy because of the development of secondary GnRH-dependent precocity or pubertal increases in gonadotropins.203,204 In such cases, a GnRH analog has been added to the regimen to restore effective control of puberty progression.203,204,212 Additional study and experience are needed to elucidate further the optimum regimens for the management of these forms of precocious puberty and the long-term effects of such therapy, and such patients should be managed in consultation with experts in the diagnosis and treatment of these conditions.203,204,206,207,213 Combinations of testolactone with flutamide or with spironolactone also have been studied as a component in the complex regimen of therapy for boys and girls with congenital adrenal hyperplasia caused by steroid 21-hydroxylase or 11-hydroxylase deficiency; the rationale for the addition of such therapy to the therapeutic regimen was similar to that for familial male precocious puberty (i.e., to control androgenic effects and accelerated growth and skeletal maturation).207
Spironolactone has been used effectively in the treatment of hirsutism in women with polycystic ovary syndrome or idiopathic hirsutism.210 In the treatment of hirsutism, spironolactone appears to exert its therapeutic effects by interfering with ovarian androgen secretion and peripheral androgen activity.210
Spironolactone has also been used as an adjunct in the treatment of myasthenia gravis and familial periodic paralysis.
Spironolactone is administered orally.265,300
Administration of spironolactone with food increases the bioavailability of the drug by approximately 90-100%.265,300 The manufacturers state that patients should establish a routine time for taking the drug with regard to meals.265,300
Spironolactone tablets should be stored in tight, light-resistant containers at a temperature less than 25°C.265
The commercially available oral suspension (CaroSpir®) is not therapeutically equivalent to spironolactone oral tablets (e.g., Aldactone®).300 In patients who require a dose exceeding 100 mg, tablets should be used; doses of CaroSpir® suspension exceeding 100 mg may result in higher than expected serum spironolactone concentrations.300 The oral suspension (CaroSpir®) should be stored at a controlled room temperature of 20-25°C but may be exposed to temperatures ranging from 15-30°C.300
Although it has frequently been recommended that spironolactone tablets be administered in 3 or 4 doses daily, more recent information suggests that 1 or 2 doses daily may be adequate.
Extemporaneously Compounded Oral Suspension
Spironolactone tablets may be pulverized and administered as an oral suspension in cherry syrup.1230
Standardized concentrations for an extemporaneously prepared oral suspension of spironolactone have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 199Multidisciplinary expert panels were convened to determine recommended standard concentrations. 199Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 199 For additional information on S4S (including updates that may be available), see [Web]199 .
Concentration Standards |
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5 mg/mL |
For the management of edema associated with hepatic cirrhosis or nephrotic syndrome in adults, the recommended initial adult dosage of spironolactone (as oral tablets) is 100 mg daily administered as a single dose or in divided doses, but initial dosage may range from 25-200 mg daily.265
When the commercially available oral suspension (CaroSpir®) is used for the treatment of edema associated with hepatic cirrhosis, the recommended initial adult dosage is 75 mg daily administered in a single dose or divided doses.300
The manufacturers state that spironolactone should be initiated in patients with cirrhosis in a hospital setting and dosage titrated slowly.265,300
Experts state that diuretics should be administered at a dosage sufficient to achieve optimal volume status and relieve congestion without inducing an excessively rapid reduction in intravascular volume, which could result in hypotension, renal dysfunction, or both.524
For the management of edema in children, a spironolactone dosage of 3.3 mg/kg daily (as oral tablets) administered as a single dose or in divided doses has been suggested. Alternatively, an initial pediatric dosage of 60 mg/m2 daily (as oral tablets) administered in divided doses has been suggested.
When used alone for the management of edema, spironolactone should be administered in the usual initial dosage for at least 5 days. If a satisfactory response is obtained, dosage may be adjusted to the optimal therapeutic or maintenance dosage.
Spironolactone/Hydrochlorothiazide Fixed-combination Therapy
The manufacturer of the fixed combination of spironolactone and hydrochlorothiazide states that the optimal dosage should be established by individual titration of the drug components.256
For the management of edema in adults, the usual maintenance dosage of the fixed combination of spironolactone and hydrochlorothiazide is 100 mg each of spironolactone and hydrochlorothiazide daily administered as a single dose or in divided doses.256 The effective dosage may range from 25-200 mg of each component daily depending on the response to the initial titration.256 In some instances, it may be beneficial to administer separate tablets of either spironolactone or hydrochlorothiazide in addition to the fixed combination of spironolactone and hydrochlorothiazide in order to provide optimal individual therapy.256
For the management of hypertension in adults, the usual initial dosage of spironolactone (as oral tablets) is 25-100 mg daily administered as a single dose or in divided doses.265,1200 The dosage may be titrated at 2-week intervals.265 Dosages exceeding 100 mg daily generally do not provide additional reductions in blood pressure.265
When the commercially available oral suspension (CaroSpir®) is used for the treatment of hypertension in adults, the recommended initial dosage is 20-75 mg daily administered in a single dose or divided doses.300 The dosage may be titrated at 2-week intervals.300 Dosages exceeding 75 mg daily generally do not provide additional reductions in blood pressure.300
For the management of hypertension in children, some experts have recommended an initial spironolactone dosage of 1 mg/kg daily (as tablets) administered as a single dose or in 2 divided doses.269 Such experts have suggested that dosage may be increased as necessary to a maximum dosage of 3.3 mg/kg (up to 100 mg) daily (as tablets) given as a single dose or in 2 divided doses.269 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Spironolactone should be administered for a minimum of 2 weeks in order to assess its effectiveness in the management of hypertension in a specific patient. Subsequent dosage should be determined by the response of the patient.
Spironolactone/Hydrochlorothiazide Fixed-combination Therapy
The manufacturer of the fixed combination of spironolactone and hydrochlorothiazide states that the optimal dosage should be established by individual titration of the drug components.256 When the fixed combination is used for the management of hypertension, the dosage will vary depending on the results of the titration of the individual drug components.256 Most patients will have an optimal response to 50-100 mg each of spironolactone and hydrochlorothiazide daily administered as a single dose or in divided doses.256
Monitoring and Blood Pressure Treatment Goals
The patient's renal function and electrolytes should be assessed 2-4 weeks after initiation of diuretic therapy.1200 Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic) may be added.1200,1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with spironolactone, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200,1216
The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 A 2017 multidisciplinary hypertension guideline from the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a blood pressure goal of less than 130/80 mm Hg in all adults, regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200,1207 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220
For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in the Thiazides General Statement 40:28.20.
For the management of severe heart failure, the manufacturer recommends an initial spironolactone dosage of 25 mg once daily (as oral tablets) in adults who have a serum potassium concentration of 5 mEq/L or less and an estimated glomerular filtration rate (eGFR) exceeding 50 mL/minute per 1.73 m2.265 In patients who tolerate this initial dosage, dosage may be increased to 50 mg once daily as clinically indicated; those who do not tolerate the initial dosage (i.e., develop hyperkalemia) may receive 25 mg once every other day.265 Alternatively, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) recommend an initial spironolactone dosage of 12.5-25 mg once daily and a maintenance dosage (after 4 weeks of therapy) of 25 mg once or twice daily (as tablets) in patients who have a serum potassium concentration of 5 mEq/L or less and adequate renal function (eGFR at least 50 mL/minute per 1.73 m2).524
For the management of edema associated with heart failure in adults, some experts recommend initiating spironolactone (oral tablets) at a low dosage (e.g., 12.5-25 mg once daily) and increasing the dosage (maximum of 50 mg daily; higher dosages may be used with close monitoring) until urine output increases and weight decreases, generally by 0.5-1 kg daily.524
The manufacturer recommends that serum potassium and renal function be monitored 1 week after initiation and then regularly thereafter; more frequent monitoring may be necessary when spironolactone is given with other drugs that cause hyperkalemia or in patients with impaired renal function.265 ACCF and AHA recommend that serum potassium and renal function be checked within 2-3 days and again 7 days after initiation of an aldosterone antagonist.524 Subsequent monitoring should be performed as needed based upon the stability of renal function and fluid status but should occur at least monthly for the first 3 months and then every 3 months thereafter.524 If hyperkalemia occurs, the dosage of spironolactone should be decreased or the drug discontinued and hyperkalemia should be treated.265 ACCF and AHA recommend withholding therapy with an aldosterone receptor antagonist if the patient's serum potassium concentration exceeds 5.5 mEq/L or if renal function worsens; therapy may be resumed at a reduced dosage after confirming resolution (for at least 72 hours) of hyperkalemia (i.e., serum potassium concentration decreases to less than 5 mEq/L) and of renal insufficiency.524 ACCF and AHA state that patients should also be specifically instructed to stop taking an aldosterone receptor antagonist if they have diarrhea or are dehydrated or if therapy with a concomitant loop diuretic is interrupted.524
When the commercially available oral suspension (CaroSpir®) is used for the management of heart failure, the manufacturer recommends an initial dosage of 20 mg once daily in adults who have a serum potassium concentration of 5 mEq/L or less and an eGFR exceeding 50 mL/minute per 1.73 m2.300 In patients who tolerate this initial dosage, dosage may be increased to 37.5 mg once daily as clinically indicated; those who develop hyperkalemia on the initial dosage may have their dosage reduced to 20 mg once every other day.300
After the diagnosis of hyperaldosteronism has been established, 100-400 mg of spironolactone (as oral tablets) may be administered daily for short-term preoperative therapy.265 When spironolactone is used for the treatment of primary hyperaldosteronism in patients unable or unwilling to undergo surgery, spironolactone may be used as long-term maintenance therapy at the lowest effective dosage determined for the individual patient.265
For the treatment of hirsutism in women with polycystic ovary syndrome or idiopathic hirsutism, the usual dosage of spironolactone is 50-200 mg daily (as oral tablets).210 Regression of hirsutism is generally evident within 2 months, maximal within 6 months, and has been maintained up to at least 16 months with continued treatment.210
In patients with cirrhosis, spironolactone should be initiated with the lowest dose and titrated slowly; patients with cirrhosis and ascites should have therapy initiated in the hospital.265,300 (See Cautions: Precautions and Contraindications.)
The manufacturer states, for the treatment of heart failure in patients with an eGFR of 30-50 mL/minute per 1.73 m2, initiation of spironolactone at a dosage of 25 mg every other day (as oral tablets) should be considered because of the risk of hyperkalemia.265 Alternatively, ACCF and AHA state that the dosage of spironolactone should be reduced in heart failure patients with marginal renal function (eGFR 30-49 mL/minute per 1.73 m2); an initial dosage of 12.5 mg once daily or every other day and a maintenance dosage of 12.5-25 mg once daily as tablets (after 4 weeks of therapy and if serum potassium is 5 mEq/L or less) has been recommended.524 The manufacturer of the commercially available spironolactone oral suspension (CaroSpir®) states in patients with heart failure and an eGFR of 30-50 mL/minute per 1.73 m2, a reduced initial dosage of 10 mg once daily (as the oral suspension) should be considered because of the risk of hyperkalemia.300 The use of an aldosterone antagonist may be harmful in patients with an eGFR less than 30 mL/minute per 1.73 m2 because of potentially life-threatening hyperkalemia or renal insufficiency.524 (See Cautions: Electrolyte and Metabolic Effects.)
In general, adverse effects with recommended dosage of spironolactone are mild and respond to withdrawal of the drug.
Electrolyte and Metabolic Effects
Patients receiving spironolactone may develop hyperkalemia.265,300 The risk of developing hyperkalemia is increased by impaired renal function or concomitant potassium supplementation, potassium-containing salt substitutes, or drugs that increase serum potassium (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists).265,300 (See Drug Interactions.) Hyperkalemia can cause cardiac irregularities that may be fatal.
Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has occurred in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function. Mild acidosis also has occurred during spironolactone therapy. Spironolactone also may cause hypochloremic alkalosis.265
Dehydration and hyponatremia manifested by a low serum sodium concentration, dry mouth, thirst, drowsiness, and lethargy may occur during spironolactone therapy, especially when spironolactone is used concomitantly with other diuretics. In patients with severe cirrhosis, dehydration and hyponatremia may be followed by further hepatic decompensation and asterixis. Hyponatremia occurs most frequently in patients with advanced cirrhosis and may be prevented by restriction of water intake, administration of corticosteroids, or administration of mannitol.
Spironolactone may cause hypomagnesemia, hypocalcemia, and hyperglycemia.265,300 Asymptomatic hyperuricemia also may occur and gout may rarely be precipitated.265,300
Sudden alterations of fluid and electrolyte balance may precipitate impaired neurologic function, worsening hepatic encephalopathy, and coma in patients with hepatic disease with cirrhosis and ascites.265
Anorexia, nausea, vomiting, diarrhea, abdominal cramping, gastritis, gastric bleeding, and ulceration have occurred during spironolactone therapy.
Headache, drowsiness, lethargy, ataxia, mental confusion, and fever have occurred during spironolactone therapy. In addition, severe fatigue and lassitude have been associated with the rapid and profound weight loss that occurs at the start of high-dose spironolactone therapy in patients with primary hyperaldosteronism.
Dermatologic and Sensitivity Reactions
Maculopapular and erythematous rashes (sometimes accompanied by eosinophilia), anaphylactic reaction, vasculitis, and urticaria have been reported rarely in patients receiving spironolactone. Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, pruritus, and chloasma have also been reported in patients receiving spironolactone therapy.265,300
Adverse effects related to the steroid-like structure of spironolactone include painful gynecomastia, decreased libido, and relative impotence in males, and menstrual irregularities, amenorrhea, postmenopausal bleeding, and breast soreness in females. Gynecomastia appears to be related to both dosage and duration of therapy (onset varies from 1-2 months to more than a year) and is usually reversible following discontinuance of spironolactone; however, some breast enlargement may rarely persist.265,300 Spironolactone may be associated with a greater risk of gynecomastia than eplerenone.1200 In the RALES study, approximately 9% of the male patients who received spironolactone (mean dosage: 26 mg once daily) developed gynecomastia.265 Carcinoma of the breast has been reported in patients receiving spironolactone; however, a causal relationship to the drug has not been established.256 Androgen-like adverse effects such as hirsutism and deepening of the voice have also been reported.
Excessive diuresis may cause symptomatic dehydration, hypotension, and worsening renal function, especially in patients who are salt-depleted or those taking an ACE inhibitor or angiotensin II receptor antagonist.265,300 Worsening of renal function also may occur when spironolactone is used in conjunction with nephrotoxic drugs (e.g., aminoglycosides, cisplatin, nonsteroidal anti-inflammatory agents [NSAIAs]).265,300
Leg cramps, leukopenia (including agranulocytosis), and thrombocytopenia have been reported during spironolactone therapy.265 Mixed cholestatic/hepatocellular toxicity, with at least one fatality, has been reported rarely with spironolactone administration.265,300
Precautions and Contraindications
When spironolactone is used as a fixed-combination preparation that includes hydrochlorothiazide, the cautions, precautions, and contraindications associated with thiazide diuretics must be considered in addition to those associated with spironolactone.
Unless spironolactone is given concomitantly with another diuretic and a corticosteroid, the concurrent use of potassium supplements should generally be avoided. Serum electrolyte, uric acid, and blood glucose concentrations should be monitored periodically in patients receiving spironolactone.265,300 The manufacturer states that serum potassium concentrations should be monitored within 1 week of initiating or titrating spironolactone therapy and regularly thereafter.265 More frequent monitoring may be necessary when spironolactone is administered with other drugs that cause hyperkalemia or in patients with renal impairment.265 Serum potassium concentrations should be checked when concomitant ACE inhibitor or angiotensin II receptor antagonist therapy is altered.265,300 The patient's volume status and renal function also should be monitored periodically while on spironolactone therapy.265 Patients should be warned to avoid excessive ingestion of potassium-rich foods or salt substitutes. If hyperkalemia, occurs, the dosage of spironolactone should be decreased or the drug discontinued and hyperkalemia should be treated.265,300
Spironolactone should be used with caution in patients with impaired renal function or hepatic disease. Spironolactone is contraindicated in patients with hyperkalemia.265,300 Some clinicians consider spironolactone to be contraindicated in patients whose serum creatinine or BUN concentration is more than twice normal. Spironolactone is also contraindicated in patients with Addison's disease or with concomitant use of eplerenone.265,300
The manufacturer states that safety and efficacy of spironolactone have not been established in pediatric patients.265,300
The use of spironolactone during pregnancy may affect the sex differentiation of a male fetus during embryogenesis.265 Studies in rats indicate that spironolactone may cause feminization of male fetuses and endocrine dysfunction in female fetuses exposed to the drug in utero.265,300 Data from published case reports and case series have not demonstrated an association of major malformations or other adverse pregnancy outcomes with spironolactone use.265,300 Because of the potential risk to the male fetus due to the antiandrogenic properties of spironolactone, the drug should be avoided during pregnancy; pregnant women who receive spironolactone should be advised of the potential risk to a male fetus.265,300
Spironolactone is not distributed into milk; however, the active metabolite, canrenone, is distributed into milk in low amounts that are expected to be clinically inconsequential.265,300 The developmental and health benefits of breastfeeding along with the mother's clinical need for spironolactone and any potential adverse effects on the breastfed child from spironolactone or from the underlying maternal condition should be considered.265
Drugs that Block the Renin-Angiotensin System
Concomitant administration of spironolactone and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist may cause severe hyperkalemia.265,300 Serum potassium concentrations should be monitored closely in patients receiving concomitant therapy with an ACE inhibitor or angiotensin II receptor antagonist and spironolactone.265,300
Drugs or Foods that Increase Serum Potassium Concentration
Concomitant use of spironolactone, potassium supplements or other substances containing potassium (e.g., salt substitutes), or potassium-rich diets may increase the risk of severe hyperkalemia as compared with spironolactone therapy alone.256,265 In general, potassium supplementation should be discontinued in patients with heart failure who are initiating spironolactone.265,300
Spironolactone should not be used concurrently with another potassium-sparing agent256 or aldosterone receptor antagonist (e.g., eplerenone) since concomitant therapy with these drugs may increase the risk of severe hyperkalemia as compared with spironolactone alone; concomitant use of spironolactone and eplerenone is contraindicated.256,265,300 Concomitant use of spironolactone and other drugs that are known to cause hyperkalemia, such as ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory agents (NSAIAs), heparin or low molecular weight heparin, or trimethoprim, may cause severe hyperkalemia.265
Worsening of renal function may occur with concomitant use; the patient's renal function and volume status should be monitored periodically.265,300
Antihypertensive and Hypotensive Agents
When used in conjunction with other diuretics or hypotensive agents, spironolactone may be additive with or may potentiate the action of these drugs. Therefore, dosage of these drugs, particularly ganglionic blocking agents, may need to be reduced by at least 50% when concomitant spironolactone therapy is instituted.
Hyperkalemic metabolic acidosis has been reported in patients who received spironolactone concurrently with cholestyramine.265,300
Worsening of renal function may occur with concomitant use; the patient's renal function and volume status should be monitored periodically.265,300
Concomitant use of spironolactone and CNS depressants, including alcohol, barbiturates, and opiate agonists, may potentiate orthostatic hypotension.256
Concomitant use of spironolactone and corticosteroids may intensify electrolyte depletion, particularly hypokalemia.256
Spironolactone and its metabolites interfere with radioimmunoassays for digoxin and increase the apparent exposure to digoxin.265,300 The extent, if any, to which spironolactone actually increases digoxin exposure is unknown.265,300 In patients receiving concomitant therapy with spironolactone and digoxin, an assay that does not interact with spironolactone should be used to measure serum digoxin concentrations.265,300
Renal clearance of lithium is decreased in patients receiving diuretics, and lithium toxicity may result.265,300 Serum lithium concentrations should be monitored periodically during concomitant spironolactone and lithium use.265,300
Nondepolarizing Neuromuscular Blocking Agents
Concomitant use of spironolactone and nondepolarizing neuromuscular blocking agents may potentially increase the neuromuscular blockade.256
Nonsteroidal Anti-inflammatory Agents
Concomitant use of spironolactone and NSAIAs (e.g., indomethacin) may cause severe hyperkalemia.256,265 NSAIAs, including aspirin, can reduce the diuretic, natriuretic, and antihypertensive effect of diuretics.265,300 When these drugs are used concomitantly, the maintenance dosage of spironolactone may need to be increased and the patient should be monitored closely to determine if the desired therapeutic effect of spironolactone is being achieved.265,300 Worsening of renal function also may occur with concomitant use; the patient's renal function and volume status should be monitored periodically.265,300
Spironolactone reportedly reduces vascular responsiveness to norepinephrine, and regional or general anesthesia should be used with caution in patients receiving spironolactone.
Tests for Plasma and Urinary Steroids
Because spironolactone metabolites produce fluorescence, the drug may interfere with fluorometric determinations of plasma and urinary 17-hydroxycorticosteroids (cortisol). Spurious plasma and urine fluorescence may persist for several days after termination of spironolactone therapy. It has been reported that spironolactone administration may also interfere with determinations of urinary 17-hydroxycorticosteroids by the Porter-Silber technique, urinary 17-ketosteroids by the Klendshoj, Feldstein and Sprague technique, and possibly urinary 17-ketogenic steroids.
Most methods of determining urinary aldosterone appear to be unaffected by spironolactone metabolites, but one report indicates that the metabolites may interfere with aldosterone radioimmunoassay procedures.
Spironolactone may cause false elevations in measurements of serum digoxin concentrations when radioimmunoassay procedures are used.265,300
Spironolactone is a synthetic steroid mineralocorticoid (aldosterone) receptor antagonist (aldosterone antagonist) that exhibits potassium-sparing diuretic and probably cardioprotective effects.215,256 265,266
Spironolactone is a nonselective mineralocorticoid receptor antagonist, as well as an androgen and progesterone receptor antagonist.215,256,265,266,267,268,300 Spironolactone exhibits magnesium- and potassium-sparing,224,230,233 natriuretic,232,247 diuretic,224,232 and hypotensive215,224,225,227 effects by competitively inhibiting the physiologic effects of the adrenocortical hormone aldosterone on the distal renal tubules, myocardium,225,226,228,232 and vasculature.232,233
Spironolactone competitively inhibits the physiologic effects of the adrenocortical hormone aldosterone on the distal renal tubules, thereby producing increased excretion of sodium chloride and water, and decreased excretion of potassium, magnesium, ammonium, titratable acid, and phosphate. Spironolactone is a potassium-sparing diuretic that has diuretic activity only in the presence of aldosterone, and its effects are most pronounced in patients with hyperaldosteronism. Spironolactone does not interfere with renal tubular transport mechanisms and does not inhibit carbonic anhydrase. Renal plasma flow and glomerular filtration rate usually are unaffected, but free water clearance may increase. Prolonged administration of spironolactone may cause increased aldosterone secretion; however, reports are conflicting. Because most sodium is reabsorbed in the proximal renal tubules, spironolactone is relatively ineffective when administered alone, and concomitant administration of a diuretic which blocks reabsorption of sodium proximal to the distal portion of the nephron, such as a thiazide or loop diuretic, is required for maximum diuretic effects. When administered with other diuretics, spironolactone produces an additive or synergistic diuretic response and decreases potassium excretion caused by the other diuretic.
Spironolactone reportedly has hypotensive activity when given to hypertensive patients. The precise mechanism of hypotensive action has not been determined, but it has been suggested that the drug may act by blocking the effect of aldosterone on arteriolar smooth muscle or by altering the extracellular-intracellular sodium gradient.
Spironolactone appears to have cardioprotective effects when given to patients with severe heart failure.215,217,218,226,228,232 The exact mechanism of the cardioprotective action of spironolactone in patients with heart failure has not been fully elucidated, but it appears to be related more to the drug's ability to competitively inhibit the physiologic effects of aldosterone on the myocardium than to its diuretic effect.215,216,217,218,224,225,226,228,232,233,247 In addition to promoting retention of sodium and excretion of magnesium and potassium, aldosterone causes sympathetic activation,216,219,232,233 parasympathetic inhibition,216,219,232 myocardial and vascular fibrosis,215,217,218,219,224,225,226,228,232,235,250,255 direct vascular damage,215,254 and baroreceptor dysfunction;215,219,232,233,235,236,237 aldosterone also impairs arterial compliance215,217,218,219,254 and apparently prevents uptake of norepinephrine by the myocardium.215,219,233 Spironolactone appears to benefit patients with heart failure by increasing myocardial norepinephrine uptake and preventing myocardial fibrosis, sodium retention, and potassium and/or magnesium excretion.215,218,225,226,228,232,233,247 In addition, preliminary studies in animals and humans suggest that spironolactone may restore baroreceptor sensitivity and modulate baroreflex function in patients with heart failure.232,235,236,237
It generally has been believed that angiotensin-converting enzyme (ACE) inhibitors would inhibit formation of aldosterone by suppressing the renin-angiotensin-aldosterone system.215 However, there is increasing evidence to suggest that plasma aldosterone concentrations may not decrease during therapy with usual dosages of ACE inhibitors in some patients and may return to pretreatment levels in others during prolonged therapy.215,218,219,223,231,232,246,251,252,253 Results of several studies indicate that the addition of spironolactone to ACE inhibitor therapy appears to augment the suppressive effect of the ACE inhibitors on aldosterone.215,216,217,218,219,220,221 In addition, although it has been suggested that concomitant administration of an ACE inhibitor and spironolactone was relatively contraindicated because of the potential for developing severe hyperkalemia,215,217,218,222 a low incidence of severe hyperkalemia has been reported in clinical studies in patients with heart failure receiving such combined therapy.215,217,218
Spironolactone exhibits antiandrogenic effects in males and females.206,208,209,210,211 The mechanism of antiandrogenic activity of spironolactone is complex and appears to involve several effects of the drug.206,208,209,210,211 Spironolactone decreases testosterone biosynthesis by inhibiting steroid 17α-monooxygenase (17α-hydroxylase) activity, possibly secondary to destruction of microsomal cytochrome P-450 in tissues with high steroid 17α-monooxygenase activity (e.g., testes, adrenals).208,209,211 The drug also appears to competitively inhibit binding of dihydrotestosterone to its cytoplasmic receptor protein, thus decreasing androgenic actions at target tissues.206,207,208,209,210,211 Spironolactone-induced increases in serum estradiol concentration also may contribute to its antiandrogenic activity, although such increases may not occur consistently;208,209,210,211 such increases appear to result from increased conversion of testosterone to estradiol.209,211 Spironolactone may have variable effects on serum 17-hydroxyprogesterone concentrations, possibly decreasing its production by inhibiting steroid 17α-monooxygenase activity or decreasing its conversion (with resultant accumulation) to androstenedione by inhibiting cytochrome P450-dependent 17α-hydroxyprogesterone aldolase (17,20-desmolase) activity.208,210 Serum progesterone concentrations may increase with the drug secondary to decreased hydroxylation (via steroid 17α-monooxygenase) to 17-hydroxyprogesterone.208 In children, compensatory increases in lutropin (luteinizing hormone, LH) and follicle-stimulating hormone (FSH) secretion can occur, probably secondary to the drug's antiandrogenic effects (i.e., a feedback response to decreasing serum testosterone concentrations and/or peripheral androgenic activity).208
Absorption of spironolactone from the GI tract depends on the formulation in which it is administered. When spironolactone is administered as oral tablets, peak plasma concentrations of spironolactone and its active metabolite canrenone are achieved 2.6 and 4.3 hours, respectively, after dosing in healthy individuals.265
When spironolactone is administered as the oral suspension (CaroSpir®), peak plasma concentrations of spironolactone are achieved 0.5-1.5 hours after dosing in healthy individuals; peak plasma concentrations of the active metabolite canrenone are reached 2.5-5 hours after dosing.300 When spironolactone (tablets or oral suspension) is administered concomitantly with food, peak serum concentrations and areas under the serum concentration-time curves (AUCs) of the drug and, to a lesser degree, its principal metabolites are increased substantially compared with the fasting state.265,300 (See Dosage and Administration: Administration.) At equivalent doses, serum concentrations of spironolactone are 15-37% higher following administration of the oral suspension (CaroSpir®) than with the oral tablets (Aldactone®)300
When administered alone, spironolactone has a gradual onset of diuretic action with the maximum effect being reached on the third day of therapy. The delay in onset may result from the time required for adequate concentrations of the drug or metabolites to accumulate. After withdrawal of spironolactone, diuresis persists for 2 or 3 days. When a thiazide diuretic is used concomitantly with spironolactone, diuresis usually occurs on the first day of therapy.
Spironolactone and canrenone, a major metabolite of the drug, are both more than 90% bound to plasma proteins.265,300
Spironolactone or its metabolites may cross the placenta. Canrenone, a major metabolite of spironolactone, is distributed into milk.265,300
Spironolactone is rapidly and extensively metabolized.265,300 Spironolactone undergoes deacetylation at its sulfur group to form 7α-thiospironolactone
The half-life of spironolactone averages 1-2 hours,265,300
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Oral | Suspension | 25 mg/5 mL | ||
Tablets, film-coated | 25 mg* | |||
Spironolactone Tablets | ||||
50 mg* | Aldactone® (scored) | Pfizer | ||
Spironolactone Tablets | ||||
100 mg* | Aldactone® (scored) | Pfizer | ||
Spironolactone Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Oral | Tablets, film-coated | 25 mg Spironolactone and Hydrochlorothiazide 25 mg* | Pfizer | |
Spironolactone and Hydrochlorothiazide Tablets | ||||
50 mg Spironolactone and Hydrochlorothiazide 50 mg | Aldactazide® (scored) | Pfizer |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
199. ASHP. Standardize 4 Safety: compounded oral liquid standards. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]
200. Overdiek HWPM, Merkus FWHM. Influence of food on the bioavailability of spironolactone. Clin Pharmacol Ther . 1986; 40:531-6. [PubMed 3769384]
201. Overdiek HWPM, Hermens WAJJ, Merkus FWHM. New insights into the pharmacokinetics of spironolactone. Clin Pharmacol Ther . 1985; 38:469-74. [PubMed 4042530]
202. Wathen CG, MacDonald T, Wise LA et al. Eosinophilia associated with spironolactone. Lancet . 1986; 1:919-20. [PubMed 2870390]
203. Laue L, Kenigsberg D, Pescovitz OH et al. Treatment of familial male precocious puberty with spironolactone and testolactone. N Engl J Med . 1989; 320:496-502. [PubMed 2492636]
204. Laue L, Jones J, Barnes KM et al. Treatment of familial male precocious puberty with spironolactone, testolactone, and desorelin. J Clin Endocrinol Metab . 1993; 76:151-5. [PubMed 8421081]
205. Kaplan SL, Grumbach MM. Pathophysiology and treatment of sexual precocity. J Clin Endocrinol Metab . 1990; 71:785-9. [PubMed 2205623]
206. Stein DT. Southwestern Internal Medicine Conference: new developments in the diagnosis and treatment of sexual precocity. Am J Med Sci . 1992; 303:53-71. [PubMed 1728875]
207. Cutler GB, Laue L. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med . 1990; 323:1806-13. [PubMed 2247119]
208. Loriaux DL, Menard R, Taylor A et al. Spironolactone and endocrine dysfunction. Ann Intern Med . 1976; 85:630-6. [PubMed 984618]
209. Rose LI, Underwood RH, Newmark SR et al. Pathophysiology of spironolactone-induced gynecomastia. Ann Intern Med . 1977; 87:398-403. [PubMed 907238]
210. Cumming DC, Yang JC, Rebar RW et al. Treatment of hirsutism with spironolactone. JAMA . 1982; 247:1295-8. [PubMed 7199587]
211. Potter C, Willis D, Sharp HL et al. Primary and secondary amenorrhea associated with spironolactone therapy in chronic liver disease. J Pediatr . 1992; 121:141-3. [PubMed 1625072]
212. Grumbach MM, Styne DM. Sexual precocity. In: Wilson JD, Foster DW, eds. Williams textbook of endocrinology. 8th ed. Philadelphia: WB Saunders; 1992:1186-1221.
213. Reviewers' comments (personal observations).
214. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health. (NIH publication No. 98-4080.)
215. Pitt B, Zannad F, Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med . 1999; 341(10):709-17. [PubMed 10471456]
216. Pitt B, Pierard LA, Bilge A et al. Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (The Randomized Aldosterone Evaluation Study (RALES). Am J Cardiol . 1996; 78:902-7. [PubMed 8888663]
217. Zannad F. Angiotensin-converting enzyme inhibitor and spironolactone combination therapy: new objectives in congestive heart failure treatment. Am J Cardiol . 1993;71:34A-9A. [PubMed 8422003]
218. Weber KT. Aldosterone and spironolactone in heart failure. N Engl J Med . 1999; 341:753-4. [PubMed 10471464]
219. Struthers AD. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in congestive heart failure. J Card Fail . 1996; 2:47-54. [PubMed 8798105]
220. Dahlström U, K.dtdson E. Captopril and spironolactone therapy for refractory congestive heart failure. Am J Cardiol . 1993; 71:29-33A.
221. Staessen J, Lijnen P, Fagard R et al. Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocr . 1981; 91:457-65. [PubMed 7035596]
222. Squibb. Capoten® (captopril) tablets prescribing information. Princeton, NJ; 1996 Apr.
223. Semplicini A, Rossi GP, Bongiovi S et al. Time course of changes in blood pressure, aldosterone and body fluids during enalapril treatment: a double-blind randomized study vs hydrochlorothiazide plus propranolol in essential hypertension. Clin Exp Pharmacol Physiol . 1986; 13:17-24. [PubMed 3011329]
224. Weber KT, Villarreal D. Role of aldosterone in congestive heart failure. Postgrad Med . 1993; 93:203-21. [PubMed 8460078]
225. Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium: fibrosis and renin-angiotensin-aldosterone system. Circulation . 1991; 83:1849-65. [PubMed 1828192]
226. MacFadyen RJ, Barr CS, Struthers AD. Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res . 1997; 35:30-4. [PubMed 9302344]
227. Swedberg K, Eneroth P, Kjekshus J et al. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation . 1990; 82:1730-36. [PubMed 2225374]
228. Brilla CG, Matsubara LS, Weber KT. Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. J Mol Cell Cardiol . 1993; 25:563-75. [PubMed 8377216]
229. Bayliss J, Norell M, Canepa-Anson R et al. Untreated heart failure: clinical and neuroendocrine effects of introducing diuretics. Br Heart J . 1987; 57:17-22. [PubMed 3541995]
230. Massry SG, Coburn JW. The hormonal and non-hormonal control of renal excretion of calcium and magnesium. Nephron . 1973; 10:66-112. [PubMed 4575905]
231. MacFadyen RJ, Lee AF, Morton JJ et al. How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure? Heart . 1999; 82:57-61.
232. Struthers AD. Why does spironolactone improve mortality over and above an ACE inhibitor in congestive heart failure? Br J Clin Pharmacol . 1999; 47:479-82.
233. Barr CS, Lang CC, Hanson J et al. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol . 1995; 76:1259-65. [PubMed 7503007]
234. Francis GS, Chu C. Compensatory and maladaptive responses to cardiac dysfunction. Curr Opin Cardiol . 1995; 10:260-7. [PubMed 7612975]
235. Yee KM, Struthers AD. Aldosterone blunts the baroreflex response in man. Clin Sci . 1998; 95:687-92. [PubMed 9831693]
236. Wang W. Chronic administration of aldosterone depresses baroreceptor reflex function in the dog. Hypertension . 1994;24:571-5. [PubMed 7960015]
237. Wang W, McClain JM, Zucker IH. Aldosterone reduces baroreceptor discharge in the dog. Hypertension . 1992;19:270-7. [PubMed 1532165]
238. Jacobs DS, DeMott, Grady HS et al, ed. Laboratory test handbook. 4th ed. Hudson: Lexi-Comp, Inc; 1996:67-8.
239. Packer M, Gottlieb SS, Blum MA. Immediate and long-term pathophysiologic mechanisms underlying the genesis of sudden cardiac death in patients with congestive heart failure. Am J Med . 1987; 82(Suppl 3A):4-9. [PubMed 2882674]
240. Packer M, Lee WH, Kessler PD et al. Role of neurohormonal mechanisms in determining survival in patients with severe chronic heart failure. Circulation . 1987; 75(Suppl IV):IV-80-IV-92.
241. Whang R. Magnesium deficiency: pathogenesis, prevalence, and clinical implications. Am J Med . 1987 ;82(suppl 3A):24-9. [PubMed 3565424]
242. Hollifield JW. Magnesium depletion, diuretics, and arrhythmias. Am J Med . 1987; 82(Suppl 3A):30-7. [PubMed 2436474]
243. Sueta CA, Clarke SW, Dunlap SH et al. Effect of acute magnesium administration on the frequency of ventricular arrhythmia in patients with heart failure. Circulation . 1994; 89:660-6. [PubMed 7508827]
244. Bashir Y, Sneddon JF, Staunton HA et al. Effects of long-term oral magnesium chloride replacement in congestive heart failure secondary to coronary artery disease. Am J Cardiol . 1993; 72:1156-62. [PubMed 8237806]
245. Eichhorn EJ, Tandon PK, DiBianco R et al. Clinical and prognostic significance of serum magnesium concentration in chronic congestive heart failure: The PROMISE Study. J Am Coll Cardiol . 1993; 21:634-40. [PubMed 8436744]
246. Anon. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Part II. Management of heart failure: approaches to the prevention of heart failure. Am J Cardiol . 1999; 83:9-38A.
247. Anon. Spironolactone for heart failure. Med Lett Drugs Ther . 1999; 41:81-2. [PubMed 10505071]
248. Juillerat L, Nussberger J, Menard J et al. Determinants of angiotensin II generation during converting enzyme inhibition. Hypertension . 1990; 16:564-72. [PubMed 2172161]
249. Pitt B. Escape of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther . 1995; 9:145-9. [PubMed 7786835]
250. Richards AM. Aldosterone antagonism in heart failure. Lancet . 1999; 354:789-90. [PubMed 10485716]
251. Johnston CI, Jackson BJ, Larmour I et al. Plasma enalapril levels and hormonal effects after short- and long-term administration in essential hypertension. Br J Clin Pharmacol . 1984; 18:233-9S.
252. Sanchez RA, Marco E, Gilbert HB et al. Natriuretic effect and changes in renal haemodynamics induced by enalapril in essential hypertension. Drugs . 1985; 30(Suppl 1):49-58. [PubMed 2994987]
253. Hodsman GP, Brown JJ, Cumming AMM et al. Enalapril in the treatment of hypertension with renal artery stenosis. BMJ . 1983; 287:1413-7. [PubMed 6315126]
254. Rocha R, Chander PN, Khann K et al. Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats. Hypertension . 1998; 31(Part 2):451-8. [PubMed 9453344]
255. Brilla CG, Pick R, Tan LB et al. Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res . 1990; 67:1355-64. [PubMed 1700933]
256. Pfizer. Aldactazide® (spironolactone with hydrochlorothiazide) tabletss prescribing information. New York, NY; 2019 Jan.
257. Digoxin interactions: spironolactone (Aldactone). In: Hansten PD, Horn JR. Drug interactions Analysis and Management. Vancouver, WA: Applied Therapeutics, Inc; 1997:240.
258. Merck. Midamor® (amiloride HCl) tablets prescribing information (dated 1996 Aug). In: Physicians' desk reference. 54th ed. Montvale, NJ: Medical Economics Company Inc; 2000:1837-8.
259. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension . 2000; 35:1021-4. [PubMed 10818056]
260. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension . 2000; 35:1019-20. [PubMed 10818055]
261. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis . 2000; 36:646-61. [PubMed 10977801]
265. Pfizer. Aldactone® (spironolactone) tablets prescribing information. New York, NY; 2018 Apr.
266. Zillich AJ, Carter BL. Eplerenone-a novel selective aldosterone blocker. Ann Pharmacother . 2002; 36:1567-76. [PubMed 12243608]
267. Fernandez MD, Carter GD, Palmer TN. The interaction of canrenone with oestrogen and progesterone receptors in human uterine cytosol. Br J Clin Pharmacol . 1983; 15:95-101. [PubMed 6849751]
268. Nirde P, Terouanne B, Gallais N et al. Antimineralocorticoid 11B-substituted spirolactones exhibit androgen receptor agonistic activity: A structure function study. Mol Pharmacol . 2001; 59:1307-13. [PubMed 11306716]
269. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics . 2004; 114(Suppl 2):555-76. [PubMed 15286277]
300. CMP Pharma, Inc. CaroSpir® (spironolactone oral suspension) prescribing information. Farmville, NC; 2017 Aug.
501. James PA, Oparil S, Carter BL et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA . 2014; 311:507-20. [PubMed 24352797]
502. Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens . 2013; 31:1281-357. [PubMed 23817082]
503. Go AS, Bauman MA, Coleman King SM et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension . 2014; 63:878-85. [PubMed 24243703]
504. Weber MA, Schiffrin EL, White WB et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich) . 2014; 16:14-26. [PubMed 24341872]
505. Wright JT, Fine LJ, Lackland DT et al. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med . 2014; 160:499-503. [PubMed 24424788]
506. Mitka M. Groups spar over new hypertension guidelines. JAMA . 2014; 311:663-4. [PubMed 24549531]
507. Peterson ED, Gaziano JM, Greenland P. Recommendations for treating hypertension: what are the right goals and purposes?. JAMA . 2014; 311:474-6. [PubMed 24352710]
508. Bauchner H, Fontanarosa PB, Golub RM. Updated guidelines for management of high blood pressure: recommendations, review, and responsibility. JAMA . 2014; 311:477-8. [PubMed 24352759]
515. Thomas G, Shishehbor M, Brill D et al. New hypertension guidelines: one size fits most?. Cleve Clin J Med . 2014; 81:178-88. [PubMed 24591473]
523. Fihn SD, Gardin JM, Abrams J et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation . 2012; 126:e354-471.
524. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation . 2013; 128:e240-327.
526. Kernan WN, Ovbiagele B, Black HR et al. Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke . 2014; :. [PubMed 24788967]
527. O'Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation . 2013; 127:e362-425.
530. Myers MG, Tobe SW. A Canadian perspective on the Eighth Joint National Committee (JNC 8) hypertension guidelines. J Clin Hypertens (Greenwich) . 2014; 16:246-8. [PubMed 24641124]
536. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl . 2012: 2: 337-414.
700. Yancy CW, Jessup M, Bozkurt B et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation . 2016; :.
701. Ponikowski P, Voors AA, Anker SD et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J . 2016; :.
703. Ansara AJ, Kolanczyk DM, Koehler JM. Neprilysin inhibition with sacubitril/valsartan in the treatment of heart failure: mortality bang for your buck. J Clin Pharm Ther . 2016; 41:119-27. [PubMed 26992459]
1200. Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension . 2018; 71:el13-e115. [PubMed 29133356]
1201. Bakris G, Sorrentino M. Redefining hypertension - assessing the new blood-pressure guidelines. N Engl J Med . 2018; 378:497-499. [PubMed 29341841]
1202. Carey RM, Whelton PK, 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association hypertension guideline. Ann Intern Med . 2018; 168:351-358. [PubMed 29357392]
1207. Burnier M, Oparil S, Narkiewicz K et al. New 2017 American Heart Association and American College of Cardiology guideline for hypertension in the adults: major paradigm shifts, but will they help to fight against the hypertension disease burden?. Blood Press . 2018; 27:62-65. [PubMed 29447001]
1209. Qaseem A, Wilt TJ, Rich R et al. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med . 2017; 166:430-437. [PubMed 28135725]
1210. SPRINT Research Group, Wright JT, Williamson JD et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med . 2015; 373:2103-16. [PubMed 26551272]
1215. de Boer IH, Bangalore S, Benetos A et al. Diabetes and Hypertension: A Position Statement by the American Diabetes Association. Diabetes Care . 2017; 40:1273-1284. [PubMed 28830958]
1216. Taler SJ. Initial treatment of hypertension. N Engl J Med . 2018; 378:636-644. [PubMed 29443671]
1220. Cifu AS, Davis AM. Prevention, detection, evaluation, and management of high blood pressure in adults. JAMA . 2017; 318:2132-2134. [PubMed 29159416]
1222. Bell KJL, Doust J, Glasziou P. Incremental benefits and harms of the 2017 American College of Cardiology/American Heart Association high blood pressure guideline. JAMA Intern Med . 2018; 178:755-7. [PubMed 29710197]
1223. LeFevre M. ACC/AHA hypertension guideline: what is new? what do we do?. Am Fam Physician . 2018; 97(6):372-3. [PubMed 29671534]
1224. Brett AS. New hypertension guideline is released. From NEJM Journal Watch website. Accessed 2018 Jun 18. [Web]
1229. Ioannidis JPA. Diagnosis and treatment of hypertension in the 2017 ACC/AHA guidelines and in the real world. JAMA . 2018; 319(2):115-6. [PubMed 29242891]
1230. Mather LK, Wickman A. Stability of extemporaneously compounded spironolactone suspensions. AJHP . 1989; 46:2040-2. [PubMed 2816959]