Potassium-Sparing Diuretics

Dana Bartlett, RN, BSN, MSN, MA, CSPI

Dana Bartlett is a professional nurse and author. His clinical experience includes 16 years of ICU and ER experience and over 20 years of as a poison control center information specialist. Dana has published numerous CE and journal articles, written NCLEX material, written textbook chapters, and done editing and reviewing for publishers such as Elsevier, Lippincott, and Thieme. He has written widely on the subject of toxicology and was a contributing editor, toxicology section, for Critical Care Nurse journal. He is currently employed at the Rocky Mountain Poison Control Center.

ABSTRACT

Potassium-sparing diuretics prevent resorption of sodium and subsequent loss of potassium at the level of the distal part of the nephron. They are considered a mild diuretic and are used for the treatment of hypertension, edema associated with cirrhosis of the liver, nephrotic syndrome, heart failure, and post-myocardial infarction heart failure. Four potassium-sparing diuretic medication are currently available in the United States - amiloride, eplerenone, spironolactone, and triamterene. The pharmacological profile of the potassium-sparing diuretics, their labeled uses, adverse effects, contraindications, and warnings, as well as patient monitoring during therapy with a potassium-sparing diuretic and patient education issues, are discussed.

1 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Policy Statement

This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses. It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities.

Continuing Education Credit Designation

This educational activity is credited for 2.5 hours. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity. Pharmacology content is 2.5 hours.

Statement of Learning Need

Health clinicians prescribing and administering diuretics for various health conditions need to be informed about the specific prescribing information for the potassium-sparing diuretics, which are categorized as antihypertensive medication. While successfully used as adjuncts to other antihypertensive medication, clinicians should be aware that they can lead to serious adverse effects in individuals with specific disease-related concerns and in the elderly.

Course Purpose

To provide health clinicians with knowledge on the prescribing information for the standard use, benefits and risks of potassium-sparing diuretic agents.

2 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Target Audience

Advanced Practice Registered Nurses and Registered Nurses (Interdisciplinary Health Team Members, including Vocational Nurses and Medical Assistants may obtain a Certificate of Completion)

Course Author & Planning Team Conflict of Interest Disclosures

Dana Bartlett, RN, BSN, MSN, MA, CSPI, William S. Cook, PhD, Douglas Lawrence, MA, Susan DePasquale, MSN, FPMHNP-BC – All have no disclosures

Acknowledgement of Commercial Support

There is no commercial support for this course.

Please take time to complete a self-assessment of knowledge, on page 4, sample questions before reading the article. Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course.

3 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1. The labeled uses of spironolactone and triamterene include treatment of edema caused by

a. liver cirrhosis, heart failure, and nephrotic syndrome b. heart failure, adrenal insufficiency and kidney failure. c. pulmonary failure, COPD, pneumonia. d. renal failure, aortic stenosis, atherosclerosis.

2. If hyperkalemia develops in a patient taking eplerenone,

a. the drug must be stopped immediately. b. the dose may need to be adjusted or stopped. c. a moderate CYP3A4 inhibitor may need to be added. d. the dose does not need to be adjusted because they are unrelated.

3. Amiloride should not be given to patients who have

a. diabetes mellitus. b. chronic obstructive pulmonary disease. c. early stage renal disease. d. ventricular failure.

4. It is recommended that the use of spironolactone be discontinued or therapy with the drug interrupted in patients who have heart failure if the serum potassium is

a. 3.0 mEq/L or the serum creatinine is > 2.8 mg/dL. b. 7.0 mEq/L or the serum creatinine is > 3.0 mg/dL. c. > 5.0 mEq/L or the serum creatinine is > 4.0 mg/dL. d. 3.8 mEq/L or the serum creatinine is > 2.5 mg/dL.

5. Central nervous system (CNS) side effects of spironolactone include all EXCEPT

a. ataxia. b. confusion. c. dizziness. d. hearing loss.

4 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Introduction

Common actions of potassium-sparing diuretics include that they inhibit sodium-potassium exchange and are effective antihypertensive agents. Current guidelines, however, do not recommend the potassium-sparing diuretics as a primary therapy for hypertension as there are other effective antihypertensive medication and comparatively little data on their use for hypertension exist. There are also important differences between the varied potassium-sparing diuretic drugs, such as medication uses, risks, and adverse effects. These diuretic drug differences are all important aspects of pharmacotherapy that clinicians should know when deciding treatment. The pharmacological profile of the potassium-sparing diuretics presented in the following sections is summarized from prescribing information for each drug.

Pharmacological Profile

All four of the potassium-sparing diuretic medications, which are also categorized as antihypertensive medication, are discussed in the following sections. Eplerenone and spironolactone are also categorized as mineralocorticoid (aldosterone) receptor antagonists, as explained later on. The pharmacological profile of the potassium-sparing diuretics are outlined in this section.

Category

• Antihypertensive • Diuretic, potassium-sparing • Mineralocorticoid (aldosterone) receptor antagonist: eplerenone, spironolactone.

5 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Labeled Uses

Hypertension

Amiloride and eplerenone have a labeled use for the treatment of hypertension. It is advised in product information that amiloride is usually used in conjunction with a loop diuretic or a thiazide diuretic.

The product information for amiloride, eplerenone, and spironolactone states that the 2014 Eighth National Joint Committee (JNC-8) guidelines for the treatment of hypertension do not recommend aldosterone antagonists as an initial treatment for hypertension.1 The American Society of Hypertension and the International Society of Hypertension practice guidelines state that amiloride can be used with other diuretics like hydrochlorothiazide to prevent the hypokalemia that can occur when diuretics are used to treat hypertension.2

The product information for eplerenone states that it is used alone or with other antihypertensives to treat high blood pressure.

Edema

Spironolactone and triamterene have a labeled use for the treatment of edema caused by cirrhosis of the liver, heart failure, and nephrotic syndrome. Prescribing information for spironolactone states that it is used to treat edema from those pathologies if other therapies have not been effective.

Triamterene has a labeled use for the treatment of idiopathic edema, steroid-induced edema, and edema caused by hyperaldosteronism.

6 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Heart Failure

Amiloride has a labeled use for the treatment of heart failure.

Post-MI Heart Failure

Eplerenone has a labeled use for the treatment of heart failure with a left ventricular ejection fraction (LVEF) < 40% after an acute MI.3 Prescribing information for eplerenone also states that for patients who have had an ST segment elevation MI (STEMI) or a non-ST-segment elevation coronary syndrome and heart failure with a LVEF < 40%, the aldosterone antagonists are a recommended therapy, if other conditions are present.4,5

Mechanism of Action

Amiloride and Triamterene

Amiloride and triamterene block sodium channels in the late distal convoluted tubule and the collecting duct of the kidneys and this inhibits sodium re-absorption. Serum sodium is decreased, this affects the function of the Na+/K+ ATPase pump, and in turn potassium excretion is decreased, as is excretion of calcium, magnesium, and hydrogen.

Eplerenone and Spironolactone

Eplerenone and spironolactone are mineralocorticoid receptor blockers. They prevent aldosterone from binding to mineralocorticoid receptors, thus preventing aldosterone from increasing sodium and water retention thereby decreasing potassium and hydrogen excretion. This competitive antagonism also appears to prevent myocardial and vascular fibrosis.

7 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Available Forms

Amiloride: 5 mg tablets, alone and combined with hydrochlorothiazide.

Eplerenone: 25 and 50 mg tablets, generic and brand name (Inspra).

Spironolactone: Tablets, generic; 25, 50, and 100 mg; tablets, brand name Aldactone; 25 and 100 mg, and; oral suspension; 25 mg/5 mL. The suspension is not therapeutically equivalent to tablets. If a patient needs a dose > 100 mg, use tablets. A dose of the suspension > 100 mg may cause a higher than expected spironolactone concentration.

Triamterene: The brand name of triamterene is Dyrenium, and it is available in 50 and 100 mg capsules. There is no generic form of triamterene available in the United States.

US Boxed Warning

Amiloride

Amiloride can cause a serum potassium level > 5.5 mEq/L. This can be fatal if not corrected, particularly so in the elderly, in patients who have diabetes, or patients who have renal impairment.

Hyperkalemia occurs in about 10% of patients when amiloride is used without a kaliuretic diuretic. Hyperkalemia occurs more often if the patient has diabetes mellitus (DM), renal impairment (recognized or not), and in the elderly. If amiloride and a thiazide diuretic are used concurrently the risk of hyperkalemia is approximately 1%-2%. (No reference is provided in the prescribing information).

8 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Serum potassium must be closely monitored when therapy with amiloride is started, when the dose is changed, or if the patient develops an illness that may cause renal dysfunction and thus affect potassium homeostasis. Drug-drug interactions can cause hyperkalemia, such as the concurrent use of amiloride and a drug that affects angiotensin.

Signs and symptoms of hyperkalemia include bradycardia, electrocardiogram (ECG) changes (i.e., tall, peaked T waves, a shortened QT interval), fatigue, flaccid paralysis of the limbs, paresthesia, shock, and weakness. If the patient develops signs/symptoms of hyperkalemia, use of the drug should be immediately discontinued and the hyperkalemia treated and corrected.

Eplerenone

There is no U.S., boxed warning for eplerenone.

Spironolactone

Spironolactone has been shown to be a tumorigen in chronic toxicity studies done with rats. A tumorigen is defined as something that can give rise to a tumor. The recommendation is to avoid unnecessary use of the drug and to use only when necessary.

Triamterene

All the potassium-sparing diuretics can cause high levels of serum potassium, i.e., ≥ 5.5 mEq/L. This adverse effect is more likely to happen if the patient has renal impairment and DM, even if there is no evidence of renal impairment, in elderly patients or in patients that are severely ill.

9 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Hyperkalemia that is not corrected can cause serious morbidity and death. Patients receiving this drug should have serum potassium levels monitored closely, particularly if the dose is changed or an illness develops that can affect renal function.

Contraindications

Amiloride

• Sensitivity to amiloride or any of the components of the preparation • Serum potassium > 5.5 mEq/L • Patients who are receiving other potassium conserving medications, or receiving potassium supplements, except in severe or refractory cases of hypokalemia • Anuria • Acute or chronic renal insufficiency • Evidence of diabetic nephropathy • Patients who have renal insufficiency and a blood urea nitrogen (BUN) > 30 mg/dL or a serum creatinine > 1.5 mg/dL or diabetes mellitus should only be given amiloride if their electrolytes and renal function can be closely monitored.

Eplerenone

• Sensitivity to the drug or any components of the preparation • Serum potassium > 5.5 mEq/L • CrCl ≤ 30 mL/minute • Concurrent use of strong CYP3A4 inhibitors, i.e., clarithromycin, itraconazole, ketaconazole, nefazodone, nelfinavir, ritonavir, troleandomycin

10 nursece4less.com nursece4less.com nursece4less.com nursece4less.com • If the patient has hypertension, eplerenone is contraindicated if there is concurrent use of a potassium sparing diuretic or a potassium supplement, CrCl < 50 mL/minute, serum creatinine > 2.0 mg/dL in men, > 1.8 mg/dL in women, or type 2 DM and microalbuminuria.

Spironolactone

• Sensitivity to the drug or to any components of the preparation • Acute renal insufficiency, anuria, and significant impairment of renal function (these contraindications are for the tablet form only) • Addison’s disease • Hyperkalemia • Concomitant use with eplerenone

Triamterene

• Hypersensitivity to triamterene or any components of the preparation • Anuria • Hyperkalemia • Severe hepatic disease • Severe or progressive kidney disease, except for nephrosis (triamterene has a labeled use for treating edema associated with nephrotic syndrome) • Co-administration with other potassium-sparing agents or any formulation that contains triamterene

Drug Warnings

Amiloride

Amiloride may decrease serum sodium and chloride levels and increase BUN, particularly if it is given concurrently with another diuretic. The patient

11 nursece4less.com nursece4less.com nursece4less.com nursece4less.com should be closely monitored for electrolyte disturbances and the dose should be adjusted to avoid dehydration.

Eplerenone

Eplerenone can cause hyperkalemia, and the risk of hyperkalemia is increased if the patient has DM, proteinuria, or renal impairment, and if the patient is taking an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a non-steroidal anti-inflammatory drug (NSAID), or a moderate CYP3A inhibitor like diltiazem or erythromycin. The patient should be monitored closely for hyperkalemia, and the risk of hyperkalemia is dose-related.3

If hyperkalemia develops, the dose of eplerenone may need to be adjusted or therapy with the drug stopped. Therapy should not be started with eplerenone if the serum potassium is > 5.5 mEq/L. If concurrent use with a moderate CYP3A4 inhibitor is necessary, the dose of eplerenone should be reduced.

Spironolactone

CNS Effects: Spironolactone may cause CNS depression, such as dizziness, headache and sedation.

Fluid and Electrolytes: The use of spironolactone may cause acidosis, BUN elevation, hyperglycemia, hyperkalemia, hypocalcemia, hypochloremic metabolic acidosis, hypomagnesemia, hyponatremia, and patients who have cirrhosis, heart failure, and/or renal disease may be more susceptible to these adverse

12 nursece4less.com nursece4less.com nursece4less.com nursece4less.com effects. Close monitoring for dehydration and electrolyte disturbances is necessary, and dosing adjustments may be needed.

Hyperuricemia and Gout: Asymptomatic hyperuricemia is possible. Precipitation of gout can occur, but this is rare.

Hyperkalemia: The risk of hyperkalemia caused by spironolactone is increased if the patient has excessive potassium intake or renal failure; if there is concomitant use some drugs, i.e., ACE inhibitors, ARBs, and NSAIDs.

Large doses of an ACE inhibitor (i.e., ≥ 10 mg daily of lisinopril) increase the risk for hyperkalemia.3 Increases in serum potassium are dose-related and if hyperkalemia occurs, dose reduction or cessation of the drug may be needed. Hyperkalemia increases with declining renal function.

Gynecomastia: Gynecomastia is related to the dose and the duration of therapy with spironolactone. Gynecomastia should reverse once the patient stops using the drug but (rarely) it can persist.

Triamterene

Fluid and electrolyte loss: Triamterene can cause a significant diuresis and with large fluid and electrolyte losses, and patients who have cirrhosis, heart failure, or renal diseases are susceptible to these adverse effects and may not tolerate them.

13 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Hyperkalemia: See the U.S., Boxed Warning.

Hypersensitivity: There have been rare reports of hypersensitivity reactions causing blood dyscrasias, idiosyncratic reactions, or liver damage.

Photosensitivity: Triamterene can cause photosensitivity.

Disease-related Concerns

Amiloride

Adrenal Insufficiency: Diuretics should be avoided for the treatment of hypertension if the patient has primary adrenal insufficiency, Addison’s disease. In these situations, it is preferable to adjust the glucocorticoid or mineralocorticoid doses and/or use another antihypertensive medication.6,7

Cirrhosis: If the patient has cirrhosis and is taking amiloride, effort should be made to ensure the patient does not develop electrolyte disorders that can precipitate hepatic encephalopathy.

Diabetes Mellitus: Amiloride should not be given to patients who have DM, if possible. If a patient has DM and amiloride must be used, the clinician should be extremely cautious and closely monitor electrolytes and renal function. Amiloride should not be given within three days of an oral glucose tolerance test.

14 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Metabolic/Respiratory Acidosis: Use amiloride cautiously if a patient is at risk for metabolic or respiratory acidosis, i.e., a patient who has cardiopulmonary disease or poorly controlled DM. In those cases, the patient’s acid-base status should be monitored.

Renal Impairment: Amiloride is mostly eliminated by the kidneys, so patients who have renal impairment have a greater risk for adverse effects.

Eplerenone

Heart Failure: Eplerenone can be used to treat heart failure, but it is advised that for this use the patient should have an estimated glomerular filtration rate (eGFR) of > 30 ml/minute/1.73 m2; the serum creatinine should be ≤ 2.5 mg/dL for men and ≤ 2.0 mg/dL for women, there has been no recent worsening of serum creatinine, the serum potassium is < 5.0 mEq/L and there has been no recent worsening of serum potassium.

The manufacturer recommends that if the serum potassium is > 6.0 mEq/L, eplerenone should be not be given.

The 2013 American College of Cardiology Foundation/America Heart Association (ACCF/AHA) heart failure treatment guidelines recommend considering discontinuing therapy with eplerenone if the serum potassium is

15 nursece4less.com nursece4less.com nursece4less.com nursece4less.com > 5.5 mEq/L or the patient’s renal function is worsening.3 These warnings were reaffirmed by the 2017 guidelines that update the 2013 guidelines, not specifically for eplerenone but for all the mineralocorticoid receptor antagonists. These guidelines also recommend avoiding concurrent therapy with an ACE inhibitor or an ARB and eplerenone, and that patients who have heart failure should be told to stop taking the drug if they have an episode of dehydration or diarrhea, or when therapy with a loop diuretic is interrupted.3

Hepatic Impairment: Eplerenone should be used with caution if the patient has hepatic impairment; and, there are no dosing recommendations. Systemic exposure to eplerenone is increased if the patient has moderate hepatic impairment, Child-Pugh class B.

Renal Impairment: The risk of hyperkalemia from eplerenone is increased if the patient has declining renal function. Eplerenone should be used cautiously if the patient has mild renal impairment and depending on the level of renal function, eplerenone use may be contraindicated.

Spironolactone

Adrenal Vein Catheterization: Spironolactone use should be stopped before adrenal vein catheterization.

Heart Failure: If spironolactone is used for treatment of heart failure, it is advised that the patient have an eGFR of > 30 mL/minute/1.73 m2, serum creatinine for men should be ≤ 2.5 mg/dL in men and ≤ 2.0 mg/dL in women and there has

16 nursece4less.com nursece4less.com nursece4less.com nursece4less.com been no recent worsening of serum creatinine, and the serum potassium is < 5.0 mEq/L and the patient has no recent history of severe hyperkalemia.3

It is recommended that the use of spironolactone be discontinued or therapy with the drug interrupted in patients who have heart failure if the serum potassium is > 5.0 mEq/L or the serum creatinine is > 4.0 mg/dL. The ACCF/AHA recommends discontinuing the use of spironolactone in these patients if the serum potassium is > 5.5 mEq/L, avoiding concurrent therapy with an ACE inhibitor, an ARB, and eplerenone, and patients who have heart failure should be told to stop taking the drug if they have an episode of dehydration or diarrhea, or when therapy with a loop diuretic is interrupted.3

Hepatic Disease: Use spironolactone cautiously if the patient has hepatic impairment as the drug may cause fluid and electrolyte imbalances that could precipitate hepatic coma.

Renal Impairment: Spironolactone tablets are contraindicated if the patient has acute renal insufficiency, anuria, or significant renal impairment. Decreased renal function and the concurrent use of large doses of ACE inhibitors and spironolactone increases the risk for hyperkalemia.3

Triamterene

17 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Diabetes: Triamterene should be used cautiously for patients who have pre-diabetes or DM, as the drug may increase blood glucose levels. In these situations, the doses of hypoglycemic drugs may need to be adjusted.

Gout: Triamterene may increase uric acids levels.

Hepatic Impairment: Triamterene should be used cautiously for patients who have severe hepatic dysfunction. Patients who have cirrhosis of the liver may develop hepatic encephalopathy from fluid and electrolyte imbalances caused by triamterene.

Kidney Stones: Triamterene should be used cautiously for patients who have kidney stones.

Cessation of Therapy: Abrupt cessation of triamterene in patients who have been taking the drug for a long time could, theoretically, cause a rebound kaliuresis. Triamterene should be gradually discontinued.

Adverse Effects

Amiloride

Adverse Effects: 1%-10%: • Central nervous system: Dizziness, fatigue, headache • Endocrine/metabolic: Dehydration, gynecomastia, hyperchloremic metabolic acidosis, hyperkalemia (up to 10%, the risk is diminished if the patient is receiving kaliuretic diuretics), hyponatremia

18 nursece4less.com nursece4less.com nursece4less.com nursece4less.com • Gastrointestinal: Abdominal pain, change in appetite, constipation, diarrhea, gas pain, nausea, vomiting • Genitourinary: Impotence • Musculoskeletal: Muscle cramps, weakness • Respiratory: Cough, dyspnea

Adverse Effects < 1%, post-marketing information, or case reports: • Alopecia • Bladder spasm • Cardiac arrhythmia • Chest pain • Dysuria • Gastrointestinal hemorrhage • Increased intraocular pressure • Jaundice • Orthostatic hypotension • Palpitation • Polyuria

Eplerenone

Adverse Effects > 10%: • Endocrine/metabolic: hyperkalemia ([cardiac failure and post-MI, > 5.5 mEq/L, 16%, ≥ 6.0 mEq/L, 6%], hypertension, > 5.0 mEq/L at a dose of 400 mg, 9% at a dose of ≤ 200 mg, ≤ 1%]), hypertriglyceridemia, 1- 15%, dose-related.

Adverse Effects 1-10%: • Central nervous system: Dizziness (3%), fatigue (2%)

19 nursece4less.com nursece4less.com nursece4less.com nursece4less.com • Endocrine/metabolic: Albuminuria (1%), gynecomastia (≤ 1%), hypercholesterolemia (≤ 1%), hyponatremia (2%, dose-related) • Gastrointestinal: Abdominal pain (1%), diarrhea (2%) • Genitourinary: Abnormal vaginal hemorrhage (≤ 2%), mastalgia (males ≤ 1%) • Renal: Increased serum creatinine (post-MI cardiac failure, 6%) • Respiratory: Cough (2%), flu-like symptoms (2%)

Adverse Effects <1%, post-marketing information, or case reports: • Angioedema • Increased BUN • Increased liver enzymes • Increased uric acid • Skin rash

Spironolactone

Adverse Effects 1-10%: • Endocrine/metabolic: Gynecomastia (9%)

Frequency Not Defined: • Cardiovascular: Vasculitis • Central nervous system: Ataxia, confusion, dizziness drowsiness, headache, lethargy • Dermatologic: Alopecia, chloasma, erythematous maculo-papular rash, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), urticaria • Endocrine/metabolic: Amenorrhea, decreased libido, electrolyte disturbances, hyperkalemia, hyponatremia, hypovolemia • Gastrointestinal: Abdominal cramps, diarrhea, gastritis, gastrointestinal hemorrhage, gastrointestinal ulcer, nausea, vomiting

20 nursece4less.com nursece4less.com nursece4less.com nursece4less.com • Genitourinary: Erectile dysfunction, impotence, irregular menses, mastalgia, post-menopausal bleeding • Hematologic/oncologic: Agranulocytosis, leukopenia, malignant neoplasm of breast, thrombocytopenia • Hepatic: Hepatotoxicity • Hypersensitivity: Anaphylaxis • Immunologic: DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome • Neuromuscular/skeletal: Leg cramps • Renal: Increased BUN, renal failure, renal insufficiency • Miscellaneous: Fever

Triamterene

Frequency of the adverse effects of triamterene has not been reported. • Central nervous system: Dizziness, fatigue, headache • Dermatologic: Skin photosensitivity, skin rash • Endocrine/metabolic: Hyperkalemia, hypokalemia, increased uric acid, metabolic acidosis • Gastrointestinal: Diarrhea, nausea, vomiting, xerostomia • Genitourinary: Azotemia • Hematologic and oncologic: Hematologic abnormality (unspecified), megaloblastic anemia, thrombocytopenia • Hepatic: Jaundice, liver enzyme disorder • Hypersensitivity: Anaphylaxis • Neuromuscular and skeletal: Weakness • Renal: Acute interstitial nephritis (rare), acute renal failure (rare), • increased blood urea nitrogen, increased serum creatinine, nephrolithiasis

21 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Dosing Adjustment: Hepatic Impairment

Amiloride • There are no recommendations for dosing adjustments if a patient has hepatic impairment.

Eplerenone

• There are no dosing recommendations for the use of the drug in patients who have hepatic impairment. • Systemic exposure to the drug is increased if the patient has moderate hepatic impairment, Child-Pugh class B.

Spironolactone

• There are no recommendations for dosing adjustments if patients have hepatic impairment. • Patients receiving spironolactone should be monitored closely for fluid and electrolyte imbalances as these can precipitate hepatic coma; use cautiously.

Triamterene

• There are no dosing adjustment recommendations for patients who have mild to moderate hepatic impairment, but this clinical situation has not been studied. • The use of triamterene is contraindicated in patients who have severe hepatic disease.

22 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Dosing Adjustment: Renal Impairment

Amiloride

• Prescribing information states that if the patient has DM, a BUN > 30 mg/dL, or a serum creatinine > 1.5 mg/dL, amiloride should be used cautiously. • Amiloride is contraindicated if the patient has anuria, acute or chronic renal insufficiency, or evidence of diabetic nephropathy. • If the patient’s creatinine clearance (CrCl) is 10-50 ml/minute, give 50% of the normal dose.8 If the Cr Cl is < 10 mL/minute, do not use amiloride.8 • The Beers criteria recommends that if the patient is > 65 years of age and has a CrCl of < 30 mL/minute, amiloride should not be used; in this situation the patient may develop hyperkalemia and/or hyponatremia.9

Eplerenone

Hypertension: If the CrCl is ≥ 50 mL/minute, no dosing adjustment is needed. If the CrCl is < 50 mL/minute, or the serum creatinine is > 2.0 mg/dL (males) or > 1.8 mg/dL (females), eplerenone is contraindicated, as the risk of hyperkalemia increases as renal function declines.

Heart Failure-Post-MI: For CrCl > 50 mL/minute, no dosing adjustment is needed. For CrCl 31-50 mL/minute, serum creatinine > 2.0 mg/dL (males) and 1.8 mg/dL (females), use the drug cautiously. If the CrCl is ≤ 30 mL/minute, do not use eplerenone.

23 nursece4less.com nursece4less.com nursece4less.com nursece4less.com For eGFR ≥ 50 mL/minute/1.73 m2, the initial dose is 25 mg a day. After 4 weeks of treatment and if the serum potassium is ≤ 5.0 mEq/L, the dose can be increased to 50 mg a day. If the eGFR is 30-49 ml/minute/1.73 m2 the initial dose is 25 mg once every other day. After 4 weeks of therapy and if the serum potassium is ≤ 5.0 mEq/L, the dose can be increased to 25 mg a day. If the eGFR < 30 ml/minute/1.73 m2, eplerenone should not be used.3

Spironolactone

The tablet form is contraindicated if the patient has anuria, acute renal impairment, or significant impairment of renal function.

The suspension form should be used cautiously for the treatment of edema and hypertension if the patient has renal impairment as this form of the drug is excreted renally. If the suspension form is used to treat heart failure, eGFR > 50 mL/minute/1.73 m2, no dosage adjustment is needed. For eGFR 30 to 50 mL/minute/1.73 m2, start therapy with 10 mg a day. For eGFR <30 mL/minute/1.73 m2, the manufacturers’ labeling does not have specific dosage adjustment recommendations.

The ACCF/AHA recommendations for the tablet form, in patients with eGFR ≥ 50 mL/minute/1.73 m2, includes an initial dose that should be 12.5 to 25 mg once a day. If after four weeks with this dose the serum potassium is ≤ 5 mEq/L), the dose can be increased to 25 mg once or twice a day. For eGFR 30 to 49 mL/minute/1.73 m2, 12.5 mg a day or every other day should be started, if after 4 weeks at this dose the serum potassium is ≤ 5 mEq/L, the dose can be increased to 12.5 to 25 mg a day, and for eGFR < 30 mL/minute/1.73 m2, spironolactone should not be used.3

24 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Triamterene

There are no dosing adjustment recommendations for patients who have mild to moderate renal impairment. The use of triamterene is contraindicated in patients who have progressive kidney disease or severe renal impairment. The use of triamterene should be avoided if the CrCl is ≤ 50 mL/minute.8

The 2015 Beers Criteria recommends avoiding using triamterene for patients who are ≥ 65 years of age and have a CrCl < 30 mL/minute; these patients would be more likely to develop hyperkalemia and hyponatremia.9

Dosing Adjustment: Heart Failure, Post-MI

Eplerenone

• Serum potassium < 5.0 mEq/L: Increase the dose from 25 mg every other day to 25 mg a day or to 50 mg a day.

• Serum potassium 5.0-5.4 mEq/L: No dosing adjustment needed.

• Serum potassium 5.5-5.9 mEq/L: Decrease dose from 50 mg a day to 25 mg a day or decrease dose from 25 mg a day to 25 mg every other day or if the dose is 25 mg a day consider stopping use of the medication.

• Serum potassium ≥ 6.0 mEq/L: Stop use of the drug until the serum potassium has decreased to 5.5 mEq/L then restart at 25 mg every other day.

An alternate approach is to withhold the drug if the serum potassium is > 5.5 mEq/L or if renal function is worsening, stop therapy until the serum

25 nursece4less.com nursece4less.com nursece4less.com nursece4less.com potassium is < 5.0 mEq/L, and consider beginning therapy again with a reduced dose after it has been confirmed that renal function has stabilized, and hyperkalemia has resolved for at least 72 hours.3

Spironolactone

Avoid using tablets > 25 mg/day in elderly patients with heart failure or with reduced renal function, i.e., a CrCl < 30 mL/minute or an eGFR ≤ 30 mL/minute/1.73 m2.3

Dosing Adjustments: Elderly/Geriatric Individuals

The Beers Criteria has been already mentioned several times. The Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, commonly called the Beers Criteria, is a list produced by the American Geriatrics Society. The Beers Criteria (named after one of its founders, Dr. Mark Beers) identifies medications that should be avoided in older adults or used with caution and close monitoring because of the risk of harmful adverse effects.

Amiloride

Geriatric patients show decreased clearance of amiloride; use with caution. Refer to adult dosing.

The Beers Criteria: Diuretics may be considered to be potentially inappropriate medications for 65 years and older because there is a potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; in elderly patients, sodium concentration should be monitored

26 nursece4less.com nursece4less.com nursece4less.com nursece4less.com closely when starting these drugs or changing the dose.9 Spironolactone

• Hypertension: Oral; no initial dosage adjustment necessary.10 • Patients ≥ 65 years: CrCl < 30 mL/minute (regardless of indication), avoid use due to the risk of hyperkalemia.9 • Avoid using tablets > 25 mg/day in elderly patients with heart failure or with reduced renal function, i.e., a CrCl < 30 mL/minute or an eGFR ≤ 30 mL/minute/1.73 m2.3

Triamterene

When treating hypertension, consider lower initial doses of triamterene and titrate to response.10 Refer to adult dosing.

The 2015 Beers Criteria recommends avoiding triamterene use for patients who are ≥ 65 years of age and have a CrCl < 30 mL/minute; these patients would be more likely to develop hyperkalemia and hyponatremia.9

Use During Pregnancy

The prescribing information for the potassium-sparing diuretics uses the A, B, C, D, X classification system to determine the risk of using these drugs during pregnancy. Category B: Animal studies show no risks, but there are no controlled studies on pregnant women. Category C: Animal studies have shown risk to the fetus, there are no controlled studies in women, or studies in women and animals are not available.

The A, B, C, D, X classification system has been replaced by the Food and Drug Administration (FDA) Pregnancy and Lactation Labeling Rule (PLLR). Clinicians and patients can use this link for information about the PLLR.

27 nursece4less.com nursece4less.com nursece4less.com nursece4less.com https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfor mation/Guidances/UCM450636.pdf.

Amiloride

Amiloride is pregnancy category B. Adverse effects have not been observed in animal reproduction studies.

Eplerenone

• Pregnancy category B • Adverse effects from eplerenone during pregnancy have been noted in some animal studies, but there is limited information of the effects of the drug during human pregnancy. • It is not recommended to use a mineralocorticoid receptor antagonist to treat uncomplicated hypertension during pregnancy.

Spironolactone

• Pregnancy category C. • Adverse events have been observed in some animal reproduction studies. • Heart failure is usually treated the same regardless if the patient is pregnant or not. However, spironolactone crosses the placenta, and spironolactone should be avoided during the first trimester because it has anti-androgenic effects.11 • Mineralocorticoid receptor antagonists are not recommended as a treatment for uncomplicated hypertension in pregnant women, and their use should be avoided in women of child-bearing age/potential.12 • Diuretics should not be used to treat edema that occurs during normal pregnancies.

28 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Triamterene • Pregnancy category C. • Adverse events have not been seen during animal studies. • Triamterene does cross the placenta and it is found in cord blood. • Triamterene should not be used to treat the edema that is considered a normal part of pregnancy.

Use During Breastfeeding

Amiloride

• It is not known if amiloride is excreted in breast milk. • Because there is a potential adverse reaction to a nursing child, amiloride should only be used during breastfeeding after considering the risk to the infant and the risks to the mother if she stops taking the drug.

Eplerenone

• It is not known if eplerenone is excreted in breast milk. • Because there is a potential of adverse reactions to a nursing child, eplerenone should only be used during breastfeeding after considering the risk to the infant and to the mother if she stops taking the drug.

Spironolactone

• Diuretics can suppress lactation and decrease milk volume. • The manufacturer recommends that the use of spironolactone during breastfeeding should consider the potential risks to the infant and the needs of the mother. If spironolactone is needed for preservation of the mother’s health, an alternate way of feeding should be considered. • A 1977 study found that the active metabolite of spironolactone was excreted in breast milk, and the dose delivered to the nursing infant was

29 nursece4less.com nursece4less.com nursece4less.com nursece4less.com ~ 0.2% of the maternal dose.13 This metabolite is carcinogenic in rats but its effects in humans is not known.

Triamterene

• It is not known if triamterene is excreted in breast milk. • Breastfeeding while taking triamterene is not recommended by the • manufacturer.

Dietary Concerns

Amiloride

• Amiloride should be taken with food or meals to prevent gastrointestinal distress. • Patients taking amiloride should not use potassium-containing salt substitutes.

Eplerenone

• Eplerenone can be taken with or without food. • Grapefruit juice increases the area under the plasma concentration-time curve (AUC) ~ 25%; dosage adjustments may be needed. • Patients taking eplerenone should avoid potassium supplements, a diet rich in potassium-containing foods, and potassium-containing salt substitutes.

Spironolactone

• Food increases the bioavailability of unmetabolized spironolactone by almost 100%. The package insert for Aldactone notes that the clinical importance of this effect is not known.14

30 nursece4less.com nursece4less.com nursece4less.com nursece4less.com • Spironolactone can be given with or without food but either way, it should be done consistently. • Excessive potassium intake should be avoided, i.e., potassium-rich foods and salt substitutes containing potassium.

Triamterene

• Triamterene can be taken with food, and it may be helpful to take it after a meal to avoid gastrointestinal distress.

Prescribing Pearls and Practical Information

Drug prescribing information contains basic facts like labeled uses, dosing, warnings, and adverse effects, and it provides essential guidelines for prescribing and/or administering. However, it lacks important details and background, some of the information can be a bit confusing and may even seem to be somewhat contradictory, and it can be complicated and difficult to go through. The prescribing information is complex and dense, and not simple or easy to read. However, the medical literature can be used to explain important aspects about using the potassium-sparing diuretics, to add clarity to the prescribing information, and to provide information regarding important aspects of using the drug that clinicians need to know.

This section expands on what was covered in the pharmacological profile and has in-depth information about the potassium-sparing diuretics. A thorough search of the medical literature was done, but some of these topics have not been extensively researched and the data that has been published about the uses, benefits, risks, and adverse effects of these drugs is often limited and/or relatively old. It is felt however that this information, even if it is sometimes scant and dated, should be provided so that clinicians know why

31 nursece4less.com nursece4less.com nursece4less.com nursece4less.com the prescribing information reads as it does and so they have a complete understanding of prescribing information.

The prescribing information that will be covered in this section is expanded on from the basic pharmacology section. If a topic covered in the basic pharmacology section is not mentioned here and there is no information available or it has been adequately explained in the above section.

Hypertension

As noted, amiloride and eplerenone have a labeled use for the treatment of hypertension and all the potassium-sparing diuretics are categorized as antihypertensive medication, but current guidelines do not recommend the potassium-sparing diuretics as a primary therapy for hypertension.

The JNC-8 guidelines state: “There were no RCTs [randomized controlled trials] of good or fair quality comparing the following drug classes to the 4 recommended classes ... aldosterone receptor antagonists (i.e., spironolactone) ... Therefore, these drug classes are not recommended as first-line therapy.”1 The only recommendation made by the JNC-8 about using a potassium-sparing diuretic for the treatment of hypertension is to add an aldosterone receptor antagonist to the treatment regimen if blood pressure is not controlled by an ARB plus a calcium channel blocker (CCB) plus a thiazide diuretic, or by an ACE inhibitor plus a CCB plus a thiazide diuretic.1

The American Society of Hypertension and the International Society of Hypertension practice guidelines (2014) state that the potassium-sparing diuretics are recommended for treating patients who have symptomatic heart failure and hypertension, and then only as part of a regimen that

32 nursece4less.com nursece4less.com nursece4less.com nursece4less.com includes an ACE inhibitor or an ARB plus a beta-blocker plus a thiazide diuretic, or if they are used to treat resistant hypertension (discussed later) in patients who are already receiving the standard three drug regimen.2

Finally, the 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 (2017) confirms the previous recommendations and it provides a rationale, as well. “Numerous classes of antihypertensive agents are available to treat high BP. Agents that have been shown to reduce clinical events should be used preferentially. Therefore, the primary agents used in the treatment of hypertension include thiazide diuretics, ACE inhibitors, ARBs, and CCBs. Although many other drugs and drug classes are available, either confirmation that these agents decrease clinical outcomes to an extent similar to that of the primary agents is lacking, or safety and tolerability may relegate their role to use as secondary agents.”15

These guidelines also state that amiloride and triamterene “... are monotherapy agents and minimally effective antihypertensive agents.”15 It is noted, however, that the use a potassium-sparing diuretic can be considered if a hypertensive patient who is taking a thiazide diuretic is hypokalemic.15

Treatment resistant hypertension has been defined by the American Heart Association (AHA) as: blood pressure [BP] that remains above goal in spite of the concurrent use of three antihypertensive agents of different classes. Ideally, one of the three agents should be a diuretic and all agents should be prescribed at optimal dose amounts.”16 Levels of plasma aldosterone can be higher in people who have treatment resistant hypertension,17 and the potassium-sparing diuretics can be an effective therapy for treatment resistant hypertension.18,19

33 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Edema

Spironolactone and triamterene have a labeled use for the treatment of edema caused by cirrhosis of the liver, heart failure, and nephrotic syndrome. The product information for spironolactone states that it is used to treat edema from those pathologies if other therapies have not been effective.

Triamterene has a labeled use for the treatment of idiopathic edema, steroid-induced edema, and edema caused by secondary hyperaldosteronism.

Liver Edema and Cirrhosis

Edema is defined as the presence of abnormally large amounts of fluid in body spaces. For patients who have hepatic disease, specifically cirrhosis, edema takes the form of ascites.

Ascites is a very common complication of liver cirrhosis, caused by damage to the portal circulation and portal hypertension, and the combination of spironolactone and a loop diuretic (usually furosemide) is the primary pharmacologic treatment of ascites caused by cirrhosis.20-22 Using the combination is preferable to using either drug as the sole therapy because: a) this approach helps prevent hyper- or hypokalemia, b) it achieves a shorter time to diuresis,20,21 c) cirrhotic ascites causes increased activity of the renin-angiotensin-aldosterone system,23 and hypokalemia is common in patients who have cirrhosis,24 and hypokalemia in cirrhotic patients can cause an increase in the liver’s production of ammonia, possibly precipitating hepatic coma.21

34 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Compared to the loop diuretics the potassium-sparing diuretics are considered weak diuretics, but cirrhosis of the liver appears to decrease the delivery of the loop diuretics to the kidney tubules, making the addition of spironolactone important for the treatment of ascites caused by cirrhosis.21

Triamterene has a labeled use for the treatment of ascites caused by cirrhosis of the liver, but there is no current information (< 20 years old) on its use for this purpose. Amiloride and eplerenone have been used to treat ascites caused by cirrhosis.25-27 However, apart from a single study of 105 patients (presented as an abstract)27 there are no trials comparing the potassium-sparing diuretics and little clinical experience with these two drugs in this clinical situation. It does appear that amiloride and eplerenone can be used if patients receiving spironolactone develop gynecomastia,21,26,27 a relatively common adverse effect of that drug.26

Nephrotic Syndrome and Edema

Nephrotic syndrome is a cluster of signs and symptoms caused by damage to the kidney; edema, hyperlipidemia, hypoalbuminemia, and proteinuria is the most prominent. Edema of the nephrotic syndrome is caused by: a) hypoalbuminemia that induces a fluid shift from the vascular bed to the interstitial spaces, and b) sodium retention, caused by the renal damage that prevents sodium excretion.

Spironolactone and triamterene have a labeled use for the treatment of edema caused by nephrotic syndrome, but they are seldom used for this purpose. The loop diuretics are the drug of choice for treating edema caused by nephrotic syndrome,28-30 and recent reviews of the treatment of nephrotic syndrome, volume overload in kidney disease, and the treatment of refractory edema do not mention using potassium-sparing diuretics.29,31,32

35 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Resistance to the loop diuretics is not uncommon in nephrotic syndrome but combining a loop diuretic and a thiazide diuretic is typically used in those situations.22,28,30 One article was found in the literature of the successful use of triamterene for treatment of edema caused by nephrotic syndrome that was unresponsive to combination diuretic therapy.22 This patient did not respond to bumetanide and chlorthalidone, but a loop diuretic and triamterene did induce diuresis. It was noted, however, that spironolactone and furosemide are a standard therapy for ascitic edema but for “... other edematous disorders the evidence for specific combinations of diuretics is less obvious...”22

Secondary Hyperaldosteronism and Edema

Triamterene has a labeled use for the treatment of edema caused by secondary aldosteronism. Secondary aldosteronism is a condition of excess aldosterone secretion. It is caused by a wide variety of pathologies including (but not limited to) cirrhosis, heart failure, nephrotic syndrome, obstructive renal artery diseases, and renal vasoconstriction caused by hypertension.33,34

High levels of aldosterone increase sodium and water retention. Hypertension is a primary sign of this disorder, and the hypertension will often respond to treatment with a mineralocorticoid receptor antagonist like spironolactone that has diuretic effects.34,35 Eplerenone can be used, and it is less likely than spironolactone to cause hyperkalemia; because it has far less binding to androgen and progesterone receptors the patients seldom develop gynecomastia and menstrual irregularities that can be caused by spironolactone.36 Articles referenced did not mention the use of triamterene for treating edema caused by secondary aldosteronism, and nothing on the subject was found in a literature search.

36 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Steroid-induced Edema and Idiopathic Edema

Triamterene has a labeled use for the treatment of steroid-induced edema and idiopathic edema. A literature search did not find any information on triamterene and steroid-induced edema or idiopathic edema.

Heart Failure

Amiloride has a labeled use for the treatment of heart failure, and eplerenone has a labeled use for the treatment of heart failure with LVEF < 40% after an acute MI.3 The prescribing information for eplerenone also states that for patients who have had an ST segment elevation MI (STEMI) or a non-ST-segment elevation coronary syndrome and heart failure with LVEF < 40%, the aldosterone antagonists are a recommended therapy, if other conditions are present.4,5

Patients who have heart failure produce an excess of aldosterone, the amount being proportional to the severity of their disease.37 High levels of aldosterone have been shown to cause and/or to be a contributing factor to several of the pathophysiological mechanisms of heart failure,37,38 and randomized, controlled trials of aldosterone receptor blockade with the aldosterone antagonists eplerenone and spironolactone have shown that these drugs reduce the need for hospitalization, improve symptoms, and increase survival.3 The use of aldosterone antagonists is considered standard therapy for the treatment of patients who have heart failure and reduced ejection fraction, and is recommended by professional organizations.3,39,40

The American College of Cardiology Foundation/American Heart Association’s (ACCF/AHA) 2013 guideline for the management of heart failure state that aldosterone antagonists are recommended to help reduce morbidity and mortality in patients who have heart failure and a reduced ejection fraction,

37 nursece4less.com nursece4less.com nursece4less.com nursece4less.com and to reduce morbidity and mortality in patients who have had an acute myocardial infarction (MI) and have a LVEF of 40% or less. However, the primary treatment in these patient populations is an ACE inhibitor or an ARB, a beta-blocker, and a diuretic.3 These 2013 guidelines also have dosing recommendations and contraindications and warnings for the use of aldosterone antagonists for people who have HFrEF; this information is outlined later in this section.

A 2017 update of the 2013 ACCF/AHA guideline written by the American College of Cardiology (ACC), the AHA, and the Heart Failure Society of America (HFSA) reaffirmed the 2013 guidelines, stating that “... (established) therapies for chronic HFrEF (heart failure with reduce ejection fraction) include... aldosterone antagonists. Aldosterone antagonists are added in patients with chronic HFrEF already receiving beta blockers and ACEI/ ARB/ARNI (angiotensin-receptor neprilysin inhibitor who do not have contraindications to this therapy.”39 In 2018 the ACC published an expert consensus paper on the treatment of heart failure, recommending that an aldosterone antagonist can be added to the treatment regimen of patients who have chronic HFrEF who are already taking an ACE inhibitor, an ARB, or an ARNI, unless there are contraindications, and with close monitoring of renal function and serum potassium.40

The current guidelines for the use of aldosterone antagonists in the treatment of heart failure, their benefits and risks, contraindications and cautions, are essentially extensions of the 2013 guidelines that were written by the ACCF/AHA. Those recommendations were based on large-scale studies of these drugs, and that source material is included in the reference list.41-46 A summary of the recommendations is provided below. The

38 nursece4less.com nursece4less.com nursece4less.com nursece4less.com incidence of hyperkalemia and the potassium-sparing diuretics is mentioned in the recommendations.

ACCF/AHA: Aldosterone Antagonist Receptors Dosing Information and Contraindications and Warnings3

Ø The serum creatinine level should be < 2.5 mg/dL for men and < 2.0 mg/dL for women before starting treatment with an aldosterone antagonist, or the eGFR should be > 30 mL/minute/1.73m2, and the serum potassium should be < 5.0 mEq/L. Hyperkalemia and impaired renal function as defined by those measures can be potentially life threatening during therapy with an aldosterone antagonist. Ø In patients who have normal renal function or mild to moderate renal impairment, serum potassium and renal function should be measured before starting therapy with an aldosterone antagonist, re-measured 2- 3 days after the first dose and again 7 days after the first dose. Ø Serum creatinine and potassium and the dosing of the drug should all be closely monitored during therapy. The schedule for laboratory tests should be based on previous tests results and the patient’s clinical status but measuring serum potassium should be done monthly for the first three months and then after that every three months, at least. If the serum potassium is > 5.5 mEq/L, discontinue treatment. Ø Hyperkalemia (serum potassium > 4.5 mEq/L) is the most significant risk of aldosterone antagonist therapy, and its occurrence in large clinical trials has been reported to 2%-5%36,37 and 24%-36% in population-based registries.39,40 (Note: These figures are from the studies used by the ACCF/AHA to form its 2013 guideline). More contemporary data confirms that hyperkalemia is a very common adverse effect from treatment with the aldosterone receptor antagonists,47,48 and it also reinforces the need to discontinue treatment with an aldosterone receptor if the serum potassium is > 5.5 mEq/L; levels above that point are clearly associated with poor outcomes like an increase in mortality rate.47,48

Post-MI Heart Failure

Eplerenone has a labeled use for the treatment of heart failure LVEF <40%) after an acute MI.3 The prescribing information for eplerenone also states that for patients who have had an ST segment elevation MI (STEMI) or a non-ST-segment elevation coronary syndrome and heart failure (LVEF <40%), the aldosterone antagonists are a recommended therapy, if

39 nursece4less.com nursece4less.com nursece4less.com nursece4less.com other conditions are present.4,5 Those conditions are no significant renal dysfunction; already receiving an ACE inhibitor and a beta-blocker; a left ventricular ejection fraction (LVEF) ≤ 40%, and; either symptomatic heart failure or DM.

It had long been known that aldosterone receptor blockade could reduce abnormal remodeling in the myocardium after an acute MI and that aldosterone receptor blockade could decrease the mortality risk from heart failure caused by left ventricular dysfunction. In 2003 Pitt et al published the results of their Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial.42 The authors found that using eplerenone, along with optimal medical therapy, decreased the rates of morbidity and mortality in patients who had had an acute MI that was complicated by left ventricular dysfunction and heart failure. Several (possible) explanations for this were given, but the authors wrote: “The mechanisms by which eplerenone provides myocardial protection in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure are not completely clear.”42

The benefits of an aldosterone receptor antagonist for this patient population, and for patients who have had a non-ST-segment elevation MI (NSTEMI), have been confirmed by later research,49,50 and the 2013 ACCF/AHA guidelines for the management of ST-elevation myocardial infarction (STEMI) and the 2014 ACC/AHA guidelines for the management of non-ST-elevation acute coronary syndromes (NSTE-ACS),4,5 and several authoritative sources support this use of the aldosterone receptors antagonists, as well.51-53

40 nursece4less.com nursece4less.com nursece4less.com nursece4less.com There are limitations/restrictions to the use of this therapeutic approach, they were previously mentioned, and they have been summarized (using information from the EPHESUS trial) in the 2013 ACCF/AHA guidelines for the management of ST-elevation myocardial infarction.4 In the original publication of the EPHESUS trial the authors did not explain their rationales for these recommendations; the information or explanations added here is intended as supplementary.

• The patient must not have significant renal impairment; the serum creatinine for men should be ≤ 2.5 mg/dL and ≤ 2.0 mg/dL: The recommendation was likely added because the risk of hyperkalemia from the potassium-sparing diuretics is increased if renal function is impaired. • The patient must be receiving an ACE inhibitor and a beta-blocker: The use of these drugs is considered standard therapy for post MI patients with heart failure, and the aldosterone receptor antagonists are • The LVEF must be ≤ 40%. • The serum potassium must be ≤ 5.0 mEq/L. The potassium-sparing diuretics and the ACE inhibitors both cause increased serum potassium, the potassium-sparing diuretics increase the hyperkalemic effects of the ACE inhibitors, and hyperkalemia can be dangerous in patients who have cardiovascular disease. • The patient must have either symptomatic heart failure or DM.

The presence of DM as a pre-requisite for the use of an aldosterone receptor antagonist in patients in the EPHESUS trial could have been because patients who have DM have a significant amount to gain from this treatment. Patients who have DM have more severe MIs and a greater risk for developing post- MI heart failure and LV dysfunction than people who do not have DM.52

41 nursece4less.com nursece4less.com nursece4less.com nursece4less.com People who have DM have a higher risk for developing coronary artery disease (CAD) and more severe, multi-vessel CAD; they are more likely to have had a prior MI, and; DM is an independent risk for heart failure, a risk that is not explained by the greater incidence of CAD and hypertension in people who have DM.52

Aldosterone and Myocardial/Vascular Fibrosis

Patients who have heart failure produce an excess of aldosterone, the amount being proportional to the severity of their disease.53 Excess levels of aldosterone have been shown to cause and/or to be a contributing factor to fibrosis of the myocardium and the vasculature, one of the pathophysiologic changes that occur during heart failure, and there is evidence that a mineralocorticoid receptor antagonist may help prevent this.53,54

Tumorigen Potential of Spironolactone

The US boxed warning for spironolactone states that in chronic toxicity studies done with rats the drug has been shown to be a tumorigen. There have been small studies suggesting that it may cause cancer in humans, specifically breast, pharyngeal, thyroid, and renal cancers.55

A recent (2017) examination of 74,272 patients who used spironolactone between 1986 and 2013 found no evidence of an increased risk for cancer (colorectal, endometrial, myelomonoblastic/-cytic leukemias, pancreatic, pharyngeal, renal cell, thyroid, and renal cell [primary outcome] and 27 other cancers [secondary outcome]) and a lower incidence of prostate cancer.55

42 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Specific Drug Use Considerations and Recommendations

Contraindications

Spironolactone:

The use of spironolactone is contraindicated in patients who have Addison’s disease, aka primal adrenal insufficiency,56,57 and although it is not listed in the prescribing information for the other aldosterone receptor antagonists, these drugs should not be used for patients who have Addison’s disease.56,57

Hyperkalemia is a common complication of Addison’s disease, making the use of potassium-sparing diuretics inappropriate.

Triamterene:

The prescribing information for triamterene regarding its use in patients who have liver disease is equivocal, stating that: a) the use of triamterene is contraindicated for patients who have severe hepatic disease, b) triamterene should be used cautiously for patients who have severe hepatic dysfunction, and c) there are no dosing adjustment recommendations for triamterene from the manufacturers for patients who have mild to moderate hepatic impairment, but this clinical situation has not been studied.

These recommendations are not explained/expanded on in the prescribing information. Several older (1983 and 1988) journal articles were found that found that triamterene pharmacokinetics were significantly changed in patients who had liver disease, i.e., plasma levels of the drug were markedly elevated,58,59 but no current information on the topic could be located. It could be assumed that these cautions are mentioned because many drugs are metabolized in the liver. In addition, volume depletion can be a precipitating cause of hepatic encephalopathy.60,61

43 nursece4less.com nursece4less.com nursece4less.com nursece4less.com The potassium-sparing diuretics do not list hepatic disease as a contraindication for their use. Prescribing information for amiloride states that there are no recommendations for dosing adjustments if a patient has hepatic impairment; for eplerenone it is stated that there are no dosing recommendations for the use of the drug in patients who have hepatic impairment, and that systemic exposure to the drug is increased if the patient has moderate hepatic impairment, Child-Pugh class B (this information is presumed to be similar to the pharmacokinetic information on triamterene that was previously discussed), and for spironolactone there are no recommendations for dosing adjustments if patients have hepatic impairment, but patients receiving spironolactone should be monitored closely for fluid and electrolyte imbalances as these can precipitate hepatic coma; use cautiously.

Drug Warnings

Spironolactone:

CNS Effects: It is stated in prescribing information contains a warning that spironolactone may cause drowsiness. This adverse effect is included in the 1%-10% frequency category of adverse effects for the drug, but nothing specific about it was found in the medical literature.

Hyperuricemia and Gout: According to the prescribing information, asymptomatic hyperuricemia is possible, and precipitation of gout can occur, but this is rare. A literature search did not lead to any references to the potassium-sparing diuretics as a cause for either hyperuricemia or gout. A population-based case-control study review published in 2014 stated that “... loop diuretics and thiazide diuretics were associated with an increased risk of incident gout, although use of potassium-sparing diuretics was not.”62 The 2012 American College of Rheumatology guideline for the treatment of

44 nursece4less.com nursece4less.com nursece4less.com nursece4less.com gout noted that loop and thiazide diuretics can cause elevated urate but potassium-sparing diuretics were not mentioned,63 and recent reviews by authoritative sources did not include potassium-sparing diuretics as potential causes for gout or hyperuricemia.64.65

Gynecomastia: Gynecomastia is defined as growth of benign glandular tissue in the male breast. The prescribing information states that gynecomastia is a dose and duration-related adverse effect of spironolactone but fortunately one that usually reverses once the patient stops taking the drug, but rarely will not.

Spironolactone binds to progesterone receptors (and this effect is increased with higher doses of the drug), and gynecomastia is definitely associated with spironolactone.26,36,66-68 The incidence has been reported to be 6.9%- 60%,41,69,70 and the risk for this adverse effect is clearly dose and duration- related; the higher the dose and the longer the course of therapy the greater the risk.69-71 The prescribing information states that spironolactone-induced gynecomastia may rarely not be reversible. No cases of this were found in the medical literature, but Braunstein, et al., (2017) wrote that if drug- induced gynecomastia has been present for more than a year, stopping the offending drug is unlikely to result in gynecomastia resolving.72

Triamterene:

Hypersensitivity: There have been rare reports of hypersensitivity reactions causing blood dyscrasias, idiosyncratic reactions, or liver damage. No information on these adverse effects was found in the medical literature.

45 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Photosensitivity: The prescribing information states that triamterene can cause photosensitivity, but no more information is provided. Photosensitivity is defined as a cutaneous disorder caused by a drug and exposure to the sun.73,74

There are two types of photosensitivity, photo-allergy and photoxicity.73,75 Photo-allergy is an allergic reaction, mediated by an immunologic effect, and phototoxicity occurs when the drug absorbs ultraviolet light and then releases it as energy that is damaging to the surrounding tissue.75

Despite the warning about triamterene and photosensitivity, there seems to be little documentation about this adverse effect. This author found one journal article,76 and a 2017 review of photosensitivity by an authoritative source did not mention triamterene or the potassium-sparing diuretics as potential causes of photosensitivity.77

Disease-Related Concerns

Amiloride:

Adrenal insufficiency: Diuretics should be avoided for the treatment of hypertension if the patient has primary adrenal insufficiency - Addison’s disease. In these situations, it is preferable to adjust the glucocorticoid or mineralocorticoid doses and/or use another anti-hypertensive.6

The diagnosis and treatment guideline for primary adrenal insufficiency published by the Endocrine Society states that aldosterone receptor antagonists like eplerenone and spironolactone are contraindicated for patients who have this disease (amiloride is not mentioned), but no explanation for this recommendation is provided.6 This recommendation regarding those two drugs was also made by Inder, et al.7

46 nursece4less.com nursece4less.com nursece4less.com nursece4less.com A 2016 review of primary adrenal insufficiency stated that spironolactone should not be used for patients who have adrenal insufficiency and are being treated with fludrocortisone (one of the primary therapies for this disease) as the aldosterone receptor antagonist will counteract the effects of the glucocorticoid; amiloride was not mentioned in this review.78 In addition, hyperkalemia is a common complication of Addison’s disease, making the use of potassium-sparing diuretics inappropriate.

Hyperkalemia is common in patients who have DM because insulin deficiency and hyperosmolarity move potassium out of the cells. Hyperkalemia is a common adverse effect of the potassium-sparing diuretics, so the use of these drugs for patients who have DM carries a risk. Monitoring of renal function in this situation is important because potassium is primarily excreted by the kidney as is amiloride.

There is no reason or rationale in amiloride prescribing information that explains the warning to avoid amiloride for three days prior to an oral glucose tolerance test. No recent information in the medical literature was found that discussed this topic.

Metabolic/respiratory Acidosis: Use amiloride cautiously if a patient is at risk for metabolic or respiratory acidosis, i.e., a patient who has cardiopulmonary disease or poorly controlled DM. In those cases, monitor acid-base status as

47 nursece4less.com nursece4less.com nursece4less.com nursece4less.com acidosis (respiratory acidosis to a lesser degree than metabolic acidosis) and potassium-sparing diuretics both cause hyperkalemia.

Eplerenone:

Diabetes Mellitus: If eplerenone is being used for a patient who has heart failure after an acute MI and the patient has DM, eplerenone should be used cautiously, especially if the patient has proteinuria. Proteinuria indicates a decline in renal function which, in turn, increases the risk for hyperkalemia. In this situation, the potassium-sparing diuretics should be used cautiously and with close monitoring of electrolytes.

Heart Failure: The 2013 ACCF/AHA heart failure treatment guidelines made many recommendations for the use of eplerenone. The rationales for some of these were previously discussed; two others will be explained here. The guidelines state that patients who have heart failure should be told to stop taking eplerenone if they have an episode of dehydration or diarrhea, or if therapy with a loop diuretic is interrupted.3

Dehydration can potentially decrease blood flow to the kidneys, and diarrhea can cause dehydration. Hypokalemia is a common adverse effect of the loop diuretics, and if that effect is removed while a patient is taking a potassium- sparing diuretic becomes dehydrated hyperkalemia could result.

It should be recalled here that DM was a pre-requisite for patients to be enrolled in the EPHESUS trial that used the aldosterone receptor antagonists, presumably because these drugs would provide a significant benefit to someone who had DM. Yet, the prescribing information for amiloride states that it should not be given to patients who have DM, if

48 nursece4less.com nursece4less.com nursece4less.com nursece4less.com possible, and the prescribing information for eplerenone states that it should be used cautiously if a patient has DM.

Possible explanations for this contradictory advice could be that the EPHEUS trial involved a specific group of patients, those who had had an acute MI, heart failure with an LVEF of ≤ 40%, and no evidence of renal impairment; the EPHESUS trial did not use amiloride, and administering a drug always involves risks and benefits that must be evaluated prior to, and during use. Also, labeling information for a drug is made by a process of negotiation between the pharmaceutical company and the Food and Drug Administration (FDA) and “Sometimes ... the process does not achieve its goals. A byproduct is ... an unwieldy and internally-inconsistent label, as has been the case with eplerenone.”79

Hepatic Impairment: Use with caution if the patient has hepatic impairment. The manufacturer does not have dosing recommendations for the use of the drug in patients who have hepatic impairment. Systemic exposure to eplerenone is increased if the patient has moderate hepatic impairment, Child-Pugh class B.

The Child-Pugh classification system measures albumin, bilirubin, and prothrombin time and assesses the severity of ascites and hepatic encephalopathy, assigns a point score to each, and the total score can be used to determine the one-year survival rate in patients who cirrhosis. No reference was found that discusses increased systemic exposure to eplerenone in patients who have Child-Pugh class B, moderate hepatic impairment.

49 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Spironolactone:

Adrenal Vein Catheterization: Spironolactone use should be stopped before adrenal vein catheterization. Adrenal vein catheterization is used to help make/confirm a diagnosis of primary aldosteronism, and the use of an aldosterone receptor antagonist can interfere with the interpretation of the test results.80

Triamterene:

Kidney Stones: Use triamterene cautiously for patients who have kidney stones. Triamterene can cause nephrolithiasis,81-83 but this is usually described as a rare adverse effect of the drug.82 There has been little written about this topic; Carey, et al., (1984) reported the incidence of triamterene- induced nephrolithiasis as 1 in 1500 to 1 in 2000 patients.83

Use During Pregnancy

The prescribing information for the potassium-sparing diuretics uses the A, B, C, D, X classification system to determine the risk of using these drugs during pregnancy.

Category B: Animal studies show no risks, but there are no controlled studies on pregnant women. Category C: Animal studies have shown risk to the fetus, there are no controlled studies in women, or studies in women and animals are not available. As mentioned already, this system has been replaced by the Food and Drug Administration (FDA) Pregnancy and Lactation Labeling Rule (PLLR).

50 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Amiloride:

Amiloride is pregnancy category B. Adverse effects have not been observed in animal reproduction studies. There are no clinical trials that have use amiloride during pregnancy.84 Amiloride can cross the placenta, but animal studies using doses much higher than would be prescribed for humans did not show adverse effects.84 Amiloride has been safely used treating hypertension in a pregnant woman with Liddle’s syndrome, a rare genetic form of salt-sensitive hypertension,84 and it has been used safely to treat pregnant women who have Bartter syndrome and Gitelman syndrome, genetic abnormalities of the renal tubules that cause a variety of metabolic abnormalities.85,86

Eplerenone:

Pregnancy category B. Adverse effects from eplerenone during pregnancy have been noted in some animal studies, but there is limited information of the effects of the drug during human pregnancy, and it is not recommended to use a mineralocorticoid receptor antagonist to treat uncomplicated hypertension during pregnancy. There have been two case reports of eplerenone being used as an adjunct for the treatment of primary aldosteronism in a pregnant woman,87,88 and a 2015 review stated that if mineralocorticoid receptor treatment is required during pregnancy eplerenone appears to be safe, not having the anti-androgenic qualities of spironolactone.89

Use During Breastfeeding

Amiloride:

It is not known if amiloride is excreted in breast milk. Because there is a potential of adverse reactions to a nursing child, amiloride should only be

51 nursece4less.com nursece4less.com nursece4less.com nursece4less.com used during breastfeeding after considering the risk to the infant and the risks to the mother is she stops taking the drug. LactMed is a database that is organized and maintained by the National Library of Medicine, and LactMed reviews and summarizes the available information about drugs and breastfeeding. LactMed states that there is no information available on using amiloride during breastfeeding, drug levels in nursing infants, or effects on nursing infants. Amiloride-induced diuresis is unlikely to be of sufficient intensity to suppress lacatation.90

Eplerenone:

It is not known if eplerenone is excreted in breast milk. Because there is a potential of adverse reactions to a nursing child, eplerenone should only be used during breastfeeding after considering the risk to the infant and the risks to the mother is she stops taking the drug. There is no information about eplerenone on the LactMed site.

Spironolactone:

Diuretics can suppress lactation and decrease milk volume. The manufacturer recommends that the use of spironolactone during breastfeeding should consider the potential risks to the infant and the needs of the mother. If spironolactone is needed for preservation of the mother’s health, an alternate way of feeding should be considered. A 1977 study found that the active metabolite of spironolactone was excreted in breast milk, and the dose delivered to the nursing infant was ~0.2% of the maternal dose.13 This metabolite is carcinogenic in rats but its effects in humans is not known.

LactMed referenced a case report of a mother who took 75 mg of spironolactone every other day while nursing, along with atenolol, bretylium,

52 nursece4less.com nursece4less.com nursece4less.com nursece4less.com propranolol, and vitamin and mineral supplements.91 The infant developed jaundice that was thought not to be related to spironolactone, the infant had normal development and weight gain in the first months of life.91 Spironolactone-induced diuresis is unlikely to be of sufficient intensity to suppress diuresis.92

Triamterene:

It is not known if triamterene is excreted in breast milk. Breastfeeding while taking triamterene is not recommended by the manufacturer. LactMed states that there is no information available on using triamterene during breastfeeding; drug levels in nursing infants, or; effects on nursing infants. Triamterene-induced diuresis is unlikely to be of sufficient intensity to suppress lactation.93

Summary

The potassium-sparing diuretics are categorized as antihypertensive medication, diuretics, potassium-sparing, and also as mineralocorticoid (aldosterone) receptor antagonists (in the case of eplerenone and spironolactone). Clinicians need to be aware that while the potassium- sparing diuretics can be used as adjuncts with other antihypertensive medication to help reduce morbidity and mortality in patients with treatment resistant hypertension and post-myocardial complications, such as edema, they can also have serious adverse side effects. They can cause hyperkalemia and this electrolyte disorder can be dangerous in patients who have cardiovascular disease.

53 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Patients taking certain medications, the elderly, patients who have diabetes mellitus, or those who have renal impairment are particularly at risk for a dangerous adverse effect. Serum electrolytes and renal function should be closely monitored in patients taking potassium-sparing diuretics and if the patient becomes hyperkalemic or develops renal impairment, treatment with the drug should be stopped or the dose reduced. The potassium-sparing diuretics should be used cautiously in all patients > 65 years of age.

Although they are categorized as antihypertensive medication, current guidelines do not recommend the potassium-sparing diuretics as a primary therapy for hypertension as there is comparatively little data on their use for hypertension and there are other effective antihypertensive medications that exist. Knowing the difference between potassium-sparing diuretics and other types of diuretics, as well as the important differences between drugs in the potassium-sparing diuretic class of drugs is important to planning medication treatment and successful outcomes. These diuretic drug differences are all important aspects of pharmacotherapy that clinicians should know when discussing treatment with patients.

GLOSSARY

• Anuria: Complete cessation of urine formation and excretion. • Ascites: Effusion and accumulation of serous fluid in the abdominal cavity • Azotemia: An excess of urea or other nitrogenous substances in the blood. • Cirrhosis: Liver disease characterized by fibrosis/non-functional liver tissue.

54 nursece4less.com nursece4less.com nursece4less.com nursece4less.com • Contract-induced nephropathy: The definition may vary from source to source, but contrast-induced nephropathy is essentially impaired renal function as measured by an increase of serum creatinine over baseline value or an increase in the absolute serum creatinine level. • Creatinine clearance: Creatinine clearance (CrCl) is a test that is used to estimate glomerular filtration rate (GFR). It is calculated by measuring serum creatinine, urine creatinine, and urine volume in 24 hours. The result can be reported in mL/min or (preferably) as mL/min/1.73 m2. Normal creatinine clearance for women is 88-128 mL/min, 97 to 137 mL/min for men. • Cytochrome P450: The cytochrome P 450 (CYP 450) enzyme system is the primary mechanism for drug metabolism. The activity of the enzymes of the CYP 450 system can be increased or inhibited, and this can have a significant effect on drug availability and activity. • Diuresis: Increased excretion of urine • Diuretic: An agent that causes/promotes diuresis. • Glomerular filtration rate: The GFR is a measurement of the sum of the filtration rates of all the functioning nephrons in both kidneys. Measuring GFR is practically very difficult as it requires considerable time and invasive procedures so CrCl is used to estimate GFR. Normal values of GFR depend on age, gender, weight, and the normal GFR is 120-130 mL/min/1.73 m2. A GFR that is < 89 indicates a level of kidney damage. • Hepatic encephalopathy/hepatic coma: An altered state of consciousness caused by liver disease. • Hypertension: A normal blood pressure should < 120 mm Hg systolic and < 80 mg Hg diastolic. Hypertension is defined as a systolic blood pressure > 140 mm Hg and a diastolic blood pressure > 90 mm Hg. The American College of Cardiologists and the American Heart Association has added to this by defining hypertension as a 24-hour mean of 125/75

55 nursece4less.com nursece4less.com nursece4less.com nursece4less.com mmHg or above, a daytime mean of 130/80 mmHg or above, or a nighttime mean of 110/65 mmHg or above. The level of blood pressure for which anti-hypertensive treatment is recommended differs depending on age and other issues, but a systolic pressure < 150-140 mm Hg and a diastolic pressure < 90 mmHg are the usual goals. • Hypersensitivity: A state of altered reaction in which the body reacts with an exaggerated and inappropriate immune response to what is, or what is perceived to be a foreign substance. • Kaliuresis: Excretion of potassium in the urine. • Natriuetic: Of or relating to natriruesis, which is defined as the urinary excretion of sodium. • Oliguria: Diminished urine production when compared to fluid intake; usually defined as < 500 mL of urine produced in 24 hours. • Orthostatic hypotension: The term orthostatic means pertaining to or caused by standing erect. Orthostatic hypotension is defined as a ≥ 20 mm Hg decline in systolic blood pressure or a ≥ 10 mm Hg decline in diastolic blood pressure after five minutes of being supine and after subsequently being erect for 2-5 minutes. • Pre-diabetes: A1C is 5.7%-6.4%; fasting plasma glucose is 100-125 mg/dL, and/or oral glucose tolerance test is 140-199 mg/dL.

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56 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1. The labeled uses of spironolactone and triamterene include treatment of edema caused by

a. liver cirrhosis, heart failure, and nephrotic syndrome. b. heart failure, adrenal insufficiency and kidney failure. c. pulmonary failure, COPD, pneumonia. d. renal failure, aortic stenosis, atherosclerosis.

2. If hyperkalemia develops in a patient taking eplerenone,

3. Amiloride should not be given to patients who have

a. diabetes mellitus. b. chronic obstructive pulmonary disease. c. early stage renal disease. d. ventricular failure.

4. It is recommended that the use of spironolactone be discontinued or therapy with the drug interrupted in patients who have heart failure if the serum potassium is

5. Central nervous system (CNS) side effects of spironolactone include all EXCEPT

a. ataxia. b. confusion. c. dizziness. d. hearing loss.

57 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 6. Eplerenone and spironolactone are ______and they prevent aldosterone from increasing sodium and water retention.

a. alpha blockers b. mineralocorticoid receptor blockers. c. calcium channel blockers d. dopamine antagonists

7. True or False: Diuretics can suppress lactation and decrease milk volume.

a. True b. False

8. ______indicates a decline in renal function which, in turn, increases the risk for hyperkalemia.

a. Hypoalbuminemia b. Proteinuria c. Hypertriglyceridemia d. Hypercholesterolemia

9. Diuretics should be avoided for the treatment of hypertension if the patient has primary adrenal insufficiency, aka Addison’s disease.

a. Primary renal insufficiency b. Heart failure c. Hyperthyroidism d. Kidney infection

10. The term orthostatic means pertaining to or caused by

a. loss of equilibrium. b. quick movement. c. standing erect. d. lying flat.

58 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 11. Although they are categorized as antihypertensives, current guidelines do not recommend the potassium-sparing diuretics as a primary therapy for hypertension because

a. of side effects of electrolyte disturbances. b. there are other effective antihypertensive medication and comparatively little data on their use for hypertension exist. c. there is low threshold for toxicity to develop. d. of the central nervous system (CNS) disturbances that can develop such as ataxia, dizziness, and headache.

12. ______is a database that is organized and maintained by the National Library of Medicine, and reviews and summarizes the available information about drugs and breastfeeding.

a. LactMed b. Category A Medication c. Category B Medication d. WHO

13. Amiloride and triamterene block sodium channels in the late distal convoluted tubule and the collecting duct of the kidneys and this inhibits

a. potassium excretion. b. sodium re-absorption. c. sodium excretion. d. euglycemia.

14. True or False: Hyperkalemia is a common complication of Addison’s disease, making the use of potassium-sparing diuretics inappropriate.

a. True b. False

15. Triamterene use in patients who have liver disease is

a. low risk with proper dose adjustment. b. contraindicated. c. safe. d. moderate risk for individuals with high hepatic impairment.

59 nursece4less.com nursece4less.com nursece4less.com nursece4less.com CORRECT ANSWERS:

1. The labeled uses of spironolactone and triamterene include treatment of edema caused by

a. liver cirrhosis, heart failure, and nephrotic syndrome

“Spironolactone and triamterene have a labeled use for the treatment of edema caused by cirrhosis of the liver, heart failure, and nephrotic syndrome.”

2. If hyperkalemia develops in a patient taking eplerenone,

b. the dose may need to be adjusted or stopped.

“If hyperkalemia develops, the dose of eplerenone may need to be adjusted or therapy with the drug stopped. Do not start therapy with eplerenone if the serum potassium is > 5.5 mEq/L. If concurrent use with a moderate CYP3A4 inhibitor is necessary, the dose of eplerenone should be reduced.”

3. Amiloride should not be given to patients who have

a. diabetes mellitus.

“Amiloride should not be given to patients who have DM, if possible. If a patient has DM and amiloride must be used, be extremely cautious and closely monitor electrolytes and renal function.”

4. It is recommended that the use of spironolactone be discontinued or therapy with the drug interrupted in patients who have heart failure if the serum potassium is

c. 5.0 mEq/L or the serum creatinine is > 4.0 mg/dL.

“It is recommended that the use of spironolactone be discontinued or therapy with the drug interrupted in patients who have heart failure if the serum potassium is > 5.0 mEq/L or the serum creatinine is > 4.0 mg/dL.”

60 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 5. Central nervous system (CNS) side effects of spironolactone include all EXCEPT

d. hearing loss.

“Spironolactone … 1-10% central nervous syste [symptoms] Ataxia, confusion, dizziness drowsiness, headache, lethargy.”

6. Eplerenone and spironolactone are ______that prevent aldosterone from increasing sodium and water retention.

b. mineralocorticoid receptor blockers

“Eplerenone and spironolactone are mineralocorticoid receptor blockers. They prevent aldosterone from binding to mineralocorticoid receptors, thus preventing aldosterone from increasing sodium and water retention thereby decreasing potassium and hydrogen excretion.”

7. True or False: Diuretics can suppress lactation and decrease milk volume.

a. True

“Diuretics can suppress lactation and decrease milk volume.”

8. ______indicates a decline in renal function which, in turn, increases the risk for hyperkalemia.

b. Proteinuria

“Proteinuria indicates a decline in renal function which, in turn, increases the risk for hyperkalemia. In this situation, the potassium-sparing diuretics should be used cautiously and with close monitoring of electrolytes.”

61 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 9. Diuretics should be avoided for the treatment of hypertension if the patient has primary adrenal insufficiency, aka Addison’s disease.

a. Primary renal insufficiency

“Diuretics should be avoided for the treatment of hypertension if the patient has primary adrenal insufficiency, known as Addison’s disease.”

10. The term orthostatic means pertaining to or caused by

c. standing erect.

“The term orthostatic means pertaining to or caused by standing erect.”

11. Although they are categorized as antihypertensives, current guidelines do not recommend the potassium-sparing diuretics as a primary therapy for hypertension because

b. there are other effective antihypertensive medication and comparatively little data on their use for hypertension exist.

“Although they are categorized as antihypertensives, current guidelines do not recommend the potassium-sparing diuretics as a primary therapy for hypertension because there are other effective antihypertensive medication and comparatively little data on their use for hypertension exist.”

12. ______is a database that is organized and maintained by the National Library of Medicine, and reviews and summarizes the available information about drugs and breastfeeding.

a. LactMed

“LactMed is a database that is organized and maintained by the National Library of Medicine, and LactMed reviews and summarizes the available information about drugs and breastfeeding.”

62 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 13. Amiloride and triamterene block sodium channels in the late distal convoluted tubule and the collecting duct of the kidneys and this inhibits

b. sodium re-absorption.

“Amiloride and triamterene block sodium channels in the late distal convoluted tubule and the collecting duct of the kidneys and this inhibits sodium re-absorption. Serum sodium is decreased,...”

14. True or False: Hyperkalemia is a common complication of Addison’s disease, making the use of potassium-sparing diuretics inappropriate.

a. True

“Hyperkalemia is a common complication of Addison’s disease, making the use of potassium-sparing diuretics inappropriate.”

15. Triamterene use in patients who have liver disease is

b. contraindicated.

“The prescribing information for triamterene regarding its use in patients who have liver disease is equivocal, stating that: a) the use of triamterene is contraindicated for patients who have severe hepatic disease; b) triamterene should be used cautiously for patients who have severe hepatic dysfunction, and c) there are no dosing adjustment recommendations for triamterene from the manufacturers for patients who have mild to moderate hepatic impairment…”

63 nursece4less.com nursece4less.com nursece4less.com nursece4less.com References

The References below include published works and in-text citations of published works that are intended as helpful material for your further reading.

1. James PA, et al. (2014). 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(5):507-520. 2. Weber MA, et al. (2014). 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(1):14-26 3. Yancy CW, et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. (2013). 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(16): e240-e327. 4. Amsterdam EA, et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons; American Association for Clinical Chemistry. (2014). 2014 AHA/ACC guideline for the management of patients with non-ST- elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [published correction appears in J Am Coll Cardiol. 2014;64(24):2645-2687. 5. O'Gara PT, et al. (2013). 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(4):e362- e425. 6. Bornstein SR, et al. (2016). Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364-389. 7. Inder WJ, Meyer C, and Hunt PJ. (2012). Management of hypertension and heart failure in patients with Addison's disease. Clin Endocrinol (Oxf). 2015;82(6):789-792. 8. Aronoff GR, et al. Drug Prescribing in RenalFailure: Dosing Guidelines for Adults and Children. 5th ed. Philadelphia, PA: American College of Physicians; 2007.

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