VA Class:CV704

AHFS Class:

• Potassium-sparing Diuretics 40:28.16

Generic Name(s):

• aMILoride Hydrochloride

• aMILoride Hydrochloride and Hydrochlorothiazide

Amiloride hydrochloride is a potassium-sparing diuretic.

Hypokalemia Induced by Kaliuretic Diuretics

Amiloride is used for its potassium-sparing effect in the treatment or prevention of hypokalemia induced by thiazide or other kaliuretic diuretics in patients with heart failure or hypertension. Although the manufacturers state that amiloride has little additive diuretic or hypotensive effect when used in usual dosages as an adjunct to kaliuretic diuretic therapy, additive effects have been observed when amiloride was administered concomitantly with hydrochlorothiazide. In the treatment of diuretic-induced hypokalemia, amiloride increases plasma and total body potassium concentrations, and decreases kaliuresis.

Although hypokalemia is common in patients receiving thiazide or other kaliuretic diuretics, especially in patients treated for prolonged periods, the need for routine use of potassium supplementation or potassium-sparing diuretics in most patients receiving diuretic therapy for uncomplicated hypertension remains to be established, but it may be unnecessary when such patients have an adequate dietary intake of potassium. Amiloride may be particularly useful for preventing diuretic-induced hypokalemia in patients in whom the clinical consequences of hypokalemia represent an important risk (e.g., patients receiving cardiac glycosides or patients with cardiac arrhythmias). Amiloride may also be particularly useful in patients with hypokalemia unresponsive to potassium supplements or in those who cannot tolerate potassium supplements.

Amiloride is effective in the treatment of thiazide-induced hypokalemia during therapy with thiazide diuretics. In one study in hypertensive patients with persistent thiazide-induced hypokalemia (i.e., serum potassium concentration less than 3.2 mEq/L), amiloride corrected and maintained serum potassium concentration within the normal range during continued hydrochlorothiazide therapy. Amiloride also corrects thiazide-induced hypokalemia when the drug is substituted for oral potassium supplements during thiazide therapy. In one study, the potassium-sparing effect of amiloride 5 mg daily was effective in preventing hypokalemia in patients receiving 25 or 50 mg of hydrochlorothiazide or chlorthalidone daily. Higher dosages of amiloride may be necessary initially to treat existing diuretic-induced hypokalemia. The potassium-sparing effect of amiloride generally persists during prolonged therapy with the drug, although it may diminish with time in some patients. In one study, tolerance to the potassium-sparing effect of 5 mg of amiloride daily was reported after 6 months of continual therapy.

The relative potency of amiloride compared with other potassium-sparing diuretics has not been clearly established. In a study comparing oral potassium supplementation with potassium-sparing diuretics in patients receiving 50 mg of hydrochlorothiazide daily, the effect of 5 mg of amiloride in maintaining serum potassium concentrations within the normal range was greater than that of 20 mEq of potassium chloride daily, about equal to that of 75 mg of triamterene daily, and less than that of 50 mg of spironolactone daily; however, total body potassium concentrations were similar during potassium chloride or potassium-sparing diuretic therapy. The potassium-sparing effect of amiloride is additive with that of spironolactone. Since the effect of amiloride is independent of aldosterone, amiloride may be effective in some patients unresponsive to spironolactone.

Edema

Amiloride is used for the management of edema, including edema associated with heart failure, hepatic cirrhosis, and hyperaldosteronism. Although amiloride has some diuretic activity, it should rarely be used alone. For the management of various types of edema, amiloride is generally used concomitantly with other more effective, rapidly acting diuretics such as thiazides, chlorthalidone, or loop diuretics (e.g., furosemide). Despite its additive effects on natriuresis, amiloride's value in the management of edema is in preventing or treating hypokalemia produced by other more potent diuretics. (See Uses: Hypokalemia Induced by Kaliuretic Diuretics.)

In several studies, when amiloride and hydrochlorothiazide were used concomitantly, the diuretic effects of these drugs were partially additive. In patients receiving amiloride and hydrochlorothiazide, amiloride increased the sodium excretion produced by hydrochlorothiazide; however, the manufacturers state that amiloride produces little additive diuresis when used concomitantly with a thiazide diuretic. In several studies in patients with edema associated with heart failure or hepatic disease, increased sodium excretion and decreased potassium excretion were observed during concomitant therapy with amiloride and hydrochlorothiazide, furosemide, or ethacrynic acid. In one long-term study in patients with severe cardiac disease receiving 30-160 mg of furosemide daily, amiloride dosages of 20 mg daily usually maintained plasma potassium concentrations within the normal ran in 2 patients who developed hypokalemia at this dosage, 40 mg of amiloride daily was required.

Heart Failure

Amiloride is generally used concomitantly with other more effective, rapidly acting diuretics (e.g., thiazides, chlorthalidone, loop diuretics) in the management of edema associated with heart failure. Most experts state that all patients with symptomatic heart failure who have evidence for, or a history of, fluid retention generally should receive diuretic therapy in conjunction with moderate sodium restriction, an agent to inhibit the renin-angiotensin-aldosterone (RAA) system (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, angiotensin-receptor-neprilysin inhibitor [ARNI]), a β-adrenergic blocking agent (β-blocker), and in selected patients, an aldosterone antagonist.524,700,713 Some experts state that because of limited and inconsistent data, it is difficult to make precise recommendations regarding daily sodium intake and whether it should vary with respect to the type of heart failure (e.g., reduced versus preserved ejection fraction), disease severity (e.g., New York Heart Association [NYHA] class), heart failure-related comorbidities (e.g., renal dysfunction), or other patient characteristics (e.g., age, race).524,723,724 The American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) state that limiting sodium intake to 1.5 g daily in patients with ACCF/AHA stage A or B heart failure may be reasonable.524 While data currently are lacking to support recommendation of a specific level of sodium intake in patients with ACCF/AHA stage C or D heart failure, ACCF and AHA state that limiting sodium intake to some degree (e.g., less than 3 g daily) in such patients may be considered for symptom improvement.524

Diuretics play a key role in the management of heart failure because they produce symptomatic benefits more rapidly than any other drugs, relieving pulmonary and peripheral edema within hours or days compared with weeks or months for cardiac glycosides, ACE inhibitors, or β-blockers.103 However, since there are no long-term studies of diuretic therapy in patients with heart failure, the effects of diuretics on morbidity and mortality in such patients are not known.524 Although there are patients with heart failure who do not exhibit fluid retention in the absence of diuretic therapy and even may develop severe volume depletion with low doses of diuretics, such patients are rare and the unique pathophysiologic mechanisms regulating their fluid and electrolyte balance have not been elucidated.103

Most experts state that loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, torsemide) are the diuretics of choice for most patients with heart failure.524 For additional information, see Heart Failure Under Uses: Edema in the Thiazides General Statement 40:28.20.

Hypertension

Amiloride has been used in the management of hypertension.500 However, because of established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes), current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics).501,502,503,504,1200 (See Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.) In addition to its diuretic and potassium-sparing effects, amiloride exhibits mild hypotensive activity. In hypertensive patients, amiloride is used concomitantly with a thiazide diuretic mainly to prevent or treat diuretic-induced hypokalemia. (See Uses: Hypokalemia Induced by Kaliuretic Diuretics.) The manufacturers state that amiloride produces little additive hypotensive activity when used concurrently with a thiazide diuretic. However, some experts state that inclusion of amiloride in combination drug regimens may be considered in patients with resistant hypertension if no contraindications exist.502 Potassium-sparing diuretics should be avoided in patients with substantial renal insufficiency.1200

Amiloride appears to exhibit greater hypotensive activity than triamterene; triamterene exerts an inconsistent hypotensive effect. Use of amiloride alone or in combination with hydrochlorothiazide has been effective in reducing systolic and diastolic blood pressure. In one study in hypertensive patients with mild to moderate hypertension (i.e., diastolic blood pressure of 95-115 mm Hg), when therapy using 5 or 10 mg daily of amiloride alone or 5 mg of amiloride and 50 mg of hydrochlorothiazide daily was compared with 50 mg daily of hydrochlorothiazide therapy alone, reductions in systolic and diastolic blood pressure occurred in all patients, but the combination of amiloride and hydrochlorothiazide was more effective in reducing systolic pressure than either drug alone. Baseline vs 12-week mean supine systolic/diastolic blood pressures were 153/101 vs 139/93 mm Hg for amiloride, 154/101 vs 134/89 mm Hg for hydrochlorothiazide, and 160/100 vs 137/90 mm Hg for combined therapy. In other patients, little, if any, additive hypotensive activity has reportedly occurred during concurrent therapy with amiloride and hydrochlorothiazide. Although amiloride also has been used in combination with other hypotensive agents (e.g., β-blockers), it has not been determined whether amiloride contributes to the hypotensive effect of these antihypertensive regimens.

For additional information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults and also see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Hyperaldosteronism

Amiloride therapy has controlled hypertension and corrected electrolyte abnormalities associated with primary hyperaldosteronism†; however, increased plasma renin activity and increased aldosterone production have also been observed. Spironolactone therapy is generally considered more effective for the management of primary hyperaldosteronism. When adrenal surgery is contraindicated or refused, or when patients are intolerant to spironolactone therapy, amiloride may be an effective alternative for the management of this condition.

Amiloride has also been used for the management of secondary hyperaldosteronism† (Bartter's syndrome) to correct hypokalemia; however, variable effects on plasma renin activity and increased aldosterone production have also been observed and may limit the usefulness of amiloride in the management of this condition.

Other Uses

Administration of amiloride in usual dosages has corrected the metabolic alkalosis produced by thiazide and other kaliuretic diuretics. In one study in patients with thiazide-induced metabolic alkalosis, total CO₂ concentrations decreased to normal values when amiloride was added to the thiazide regimen.

Amiloride has been used in combination with hydrochlorothiazide in patients with recurrent calcium nephrolithiasis†. In one long-term study, the administration of amiloride and hydrochlorothiazide resulted in a decrease in urinary calcium excretion in most patients with hypercalciuria; however, the effect of amiloride therapy alone on urinary calcium excretion in these patients has not been determined.

Amiloride has been used effectively for the management of lithium-induced polyuria† (secondary to lithium-induced nephrogenic diabetes insipidus).100 (See Drug Interactions: Lithium.)

Administration

Amiloride hydrochloride is administered orally, preferably with food to decrease adverse GI effects. Although amiloride hydrochloride may be used alone, the drug is generally administered concomitantly with a kaliuretic diuretic.

Dosage

Dosage of amiloride hydrochloride should be individualized according to patient requirements and response.

Hypertension

When amiloride hydrochloride is used to prevent or treat hypokalemia induced by kaliuretic diuretics in patients with hypertension, the usual initial adult dosage is 5 mg daily, added to the usual antihypertensive dosage regimen of a kaliuretic diuretic (e.g., hydrochlorothiazide). Amiloride hydrochloride dosage may be increased to 10 mg daily, if necessary. If hypokalemia persists after an adequate trial of 10 mg daily, amiloride hydrochloride dosage may be increased to 15 and then 20 mg daily with careful monitoring of serum electrolytes; however, dosages exceeding 10 mg daily usually are not necessary, and there is little controlled clinical experience with dosages exceeding 10 mg daily. Some experts state the usual dosage range is 5-10 mg daily (given as a single dose or in 2 divided doses).1200 Other clinicians have reported that the maximum effective dosage of amiloride hydrochloride in adults may be as high as 40 mg daily.

If it is considered necessary to use amiloride hydrochloride alone, the drug may be administered following these same general dosage guidelines; however, because of an increased risk of hyperkalemia when amiloride hydrochloride is used alone compared with combination therapy that includes a kaliuretic diuretic, amiloride hydrochloride dosage should be carefully titrated and serum electrolytes closely monitored.

The commercially available preparation containing amiloride hydrochloride in fixed combination with hydrochlorothiazide generally is not used initially, although the fixed-combination can be used for initial therapy in selected patients in whom the potential development of thiazide-induced hypokalemia cannot be risked. Dosage usually should first be adjusted by administering each drug separately. If it is determined that the optimum maintenance dosage corresponds to the ratio in a commercial combination preparation, the fixed combination may be used.

Monitoring and Blood Pressure Treatment Goals

The patient's renal function and electrolytes should be assessed 2-4 weeks after initiation of diuretic therapy.1200 Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug(s) adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved after dosage titration, another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, calcium-channel blocker) may be added; if target blood pressure is still not achieved, a third drug may be added.1200,1216 (See Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.) In patients who develop unacceptable adverse effects with amiloride, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200,1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 A 2017 multidisciplinary hypertension guideline from the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommend a blood pressure goal of less than 130/80 mm Hg in all adults, regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200,1207 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

Heart Failure

When amiloride hydrochloride is used to prevent or treat hypokalemia induced by kaliuretic diuretics in patients with heart failure, the usual initial adult dosage is 5 mg daily, added to the usual diuretic dosage regimen of a kaliuretic diuretic (e.g., hydrochlorothiazide). Amiloride hydrochloride dosage may be increased to 10 mg daily, if necessary. If hypokalemia persists after an adequate trial of 10 mg daily, amiloride hydrochloride dosage may be increased to 15 and then 20 mg daily with careful monitoring of serum electrolytes; however, dosages exceeding 10 mg daily usually are not necessary, and there is little controlled clinical experience with dosages exceeding 10 mg daily. Some experts recommend a maximum total daily dosage of 20 mg.524

For the management of fluid retention (e.g., edema) associated with heart failure, experts state that diuretics should be administered at a dosage sufficient to achieve optimal volume status and relieve congestion without inducing an excessively rapid reduction in intravascular volume, which could result in hypotension, renal dysfunction, or both.524

Following initial diuresis with a kaliuretic diuretic in patients with heart failure, potassium loss may decrease and the need for amiloride hydrochloride therapy should be reevaluated. Subsequent dosage adjustment may be necessary in these patients, or therapy with amiloride hydrochloride may be used intermittently. Some clinicians recommend that in any disease state, following initial diuresis with a kaliuretic diuretic, amiloride hydrochloride dosage should be reduced to the lowest effective level.

Lithium-induced Polyuria

Although amiloride generally should not be used concomitantly with lithium, amiloride hydrochloride dosages of 5-10 mg twice daily have been effective in the management of lithium-induced polyuria in adults†.100 (See Drug Interactions: Lithium.)

Pediatric Dosage

Although safety and efficacy of amiloride hydrochloride have not been established in children, a dosage of 0.625 mg/kg daily has been used in children weighing 6-20 kg†.

If amiloride hydrochloride is used for the management of hypertension in children†, some experts have recommended an initial dosage of 0.4-0.625 mg/kg once daily.111 Such experts have suggested that dosage may be increased as necessary to a maximum dosage of 20 mg once daily.111 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Amiloride is generally well tolerated, and except for hyperkalemia, serious adverse effects occur infrequently. Mild adverse effects occur in about 20% of patients receiving amiloride, but a causal relationship to the drug has not been established for many of these effects. The manufacturers state that the overall frequency of mild adverse effects is similar to that of hydrochlorothiazide. Nausea, anorexia, abdominal pain, flatulence, and mild rash are probably related to amiloride. Many other adverse effects associated with amiloride therapy are probably caused by diuresis and/or the underlying cardiovascular disease being treated.

Clinical trials have not shown an increased risk of adverse reactions during concomitant therapy with amiloride and hydrochlorothiazide compared with therapy with either drug alone. If amiloride is used concurrently with hydrochlorothiazide or another diuretic, the cautions, precautions, and contraindications associated with the other diuretic must be considered in addition to those associated with amiloride.

Hyperkalemia

The potassium-sparing effect of amiloride may cause hyperkalemia, which has resulted in life-threatening cardiac arrhythmias in some patients. Hyperkalemia (i.e., serum potassium concentration greater than 5.5 mEq/L) occurs in about 10% of patients receiving amiloride without a kaliuretic diuretic (e.g., hydrochlorothiazide). The frequency of amiloride-induced hyperkalemia is greater in patients with renal insufficiency or diabetes mellitus (with or without renal insufficiency) and in geriatric patients. When amiloride is administered concomitantly with a thiazide diuretic to patients without these complications, hyperkalemia occurs in about 1-2% of patients.

Although amiloride therapy without a kaliuretic diuretic has been associated with hyperkalemia (serum potassium concentration greater than 6 mEq/L) in some patients with ascites associated with hepatic disease, hyperkalemia probably resulted from concurrent administration of amiloride and a potassium supplement or from administration of amiloride to patients with preexisting renal disease.

Hyperkalemia has been reported when amiloride was administered concurrently with kaliuretic diuretics (e.g., furosemide, ethacrynic acid, hydrochlorothiazide), but other predisposing factors were usually present in these patients. Some clinicians have reported the development of severe hyperkalemia with associated ECG changes in geriatric patients receiving amiloride and hydrochlorothiazide. The age of the patients and other predisposing factors (e.g., preexisting renal insufficiency) probably contributed to the development of hyperkalemia in these patients.

Hyperkalemia has been reported with the use of amiloride in diabetic patients with or without renal impairment. A similar effect has been reported in diabetic patients receiving triamterene. In one study in diet-controlled diabetic patients with normal renal function, hyperkalemia did not develop during amiloride therapy. The development of hyperkalemia in diabetic patients may be related to abnormalities of the renin-angiotensin-aldosterone system and intracellular and extracellular distribution of potassium. Amiloride may be safe and effective in patients with diet-controlled diabetes mellitus and normal renal function, but should be avoided in patients with insulin-dependent diabetes mellitus. (See Cautions: Precautions and Contraindications.)

Signs or symptoms of hyperkalemia include paresthesia, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock, and ECG abnormalities. ECG changes associated with hyperkalemia are mainly characterized by tall, peaked T waves or elevations since previous tracings. Lowering of the R wave and increased depth of the S wave, widening or absence of the P wave, progressive widening of the QRS complex, prolongation of the PR interval, and/or depression of the ST segment may also occur. ECG changes do not usually occur in patients who develop mild hyperkalemia during amiloride therapy.

If hyperkalemia occurs in patients receiving amiloride, the drug should be discontinued immediately. When the serum potassium concentration exceeds 6.5 mEq/L, specific measures should be instituted to correct the hyperkalemia. (See Acute Toxicity: Treatment.) Patients with persistent hyperkalemia may require dialysis.

Other Electrolyte Effects

When amiloride is used without another diuretic, it generally has little effect on electrolytes other than potassium; however, electrolyte disturbance (e.g., hyponatremia or hypochloremia) may occur when amiloride is used with other diuretics. Hypochloremia usually does not require specific treatment except in patients with severe hepatic or renal disease. In patients who are sodium depleted, appropriate replacement therapy is recommended. Dilutional hyponatremia may occur during combined therapy with amiloride and hydrochlorothiazide in edematous patients during hot weather; in these patients, hyponatremia can generally be treated with water restriction rather than with replacement of sodium chloride except in rare instances when hyponatremia is life-threatening.

Despite amiloride's potassium-sparing effect, hypokalemia has developed in patients receiving amiloride with other diuretics. The manufacturers state that amiloride usually prevents the hypokalemia resulting from thiazide diuretics; however, some clinicians using the fixed-dose combination of amiloride and hydrochlorothiazide have questioned whether 5 mg of amiloride is sufficient to counteract the potassium loss produced by 50 mg of hydrochlorothiazide. Hypokalemia may sensitize patients to the toxic effects of cardiac glycosides (e.g., increased ventricular irritability). The risk of hypokalemia may be especially important in patients undergoing cardiac surgery since postoperative hypokalemia is a frequent occurrence.

GI Effects

Adverse GI effects of amiloride reportedly occurring in 3-8% of patients include nausea, vomiting, anorexia, and diarrhea. Abdominal pain, gas pain, appetite changes, and constipation reportedly occur in about 1-3% of patients. Flatulence, GI bleeding, abdominal bloating, GI disturbance, heartburn, and dyspepsia occur less frequently. Reactivation of latent peptic ulcer has been observed during amiloride therapy; however, a causal relationship to the drug has not been established.

Metabolic Effects

Metabolic acidosis with hyperkalemia has been reported in several patients receiving amiloride. Since shifts in acid-base balance affect the ratio of extracellular-to-intracellular potassium, metabolic acidosis may potentiate the hyperkalemic effect of amiloride. In one patient receiving concomitant therapy with amiloride and hydrochlorothiazide, metabolic acidosis developed with severe hyperkalemia. Although concurrent use of indomethacin in this patient may have contributed to the development of acidosis and hyperkalemia, acid-base balance was restored when therapy with amiloride and hydrochlorothiazide was discontinued.

Patients with cardiopulmonary disease or uncontrolled diabetes mellitus are predisposed to developing metabolic or respiratory acidosis, and amiloride should be used with caution in these patients. (See Cautions: Precautions and Contraindications.)

Renal Effects

Transient elevations in BUN or serum creatinine concentration have occurred during amiloride therapy. Transient elevations in BUN concentration during treatment with amiloride are probably attributable to rapid contraction of the extracellular fluid volume during vigorous diuresis with another diuretic. Increased BUN concentration has occurred most frequently during forced diuresis in debilitated patients who have hepatic cirrhosis with ascites and metabolic alkalosis or in those who have resistant edema. When amiloride is used with other diuretics in these predisposed patients, BUN concentration should be carefully monitored. Although elevation of serum creatinine usually indicates some decrease in renal function, it has been suggested by at least one clinician that increased serum creatinine concentration during amiloride therapy is not indicative of nephrotoxicity, but may result from inhibition of active tubular secretion and decreased urinary excretion of creatinine. At least one case of interstitial nephritis has been reported during combined therapy with amiloride and hydrochlorothiazide; however, a causal relationship to the drugs has not been established.

Abnormal renal function test results during amiloride therapy are usually transient and have been reversed in some patients following discontinuance of the drug by substituting spironolactone for amiloride.

Cardiovascular Effects

Adverse cardiovascular effects such as angina pectoris, orthostatic hypotension, palpitations, and cardiac arrhythmias (usually associated with electrolyte abnormalities) reportedly occur in 1% or less of patients treated with amiloride; cardiac arrhythmias have been reported in greater than 1% of patients receiving therapy with amiloride and hydrochlorothiazide.

Hepatic Effects

Jaundice reportedly occurs in 1% or less of patients receiving amiloride. In patients with preexisting, severe hepatic disease, amiloride, like other diuretics, has been associated with the development of hepatic encephalopathy manifested by tremors, confusion, coma, and increased jaundice. The frequency of amiloride-associated encephalopathy in these patients is reportedly similar to that during therapy with other diuretics.

Abnormalities of liver function test results, (e.g., transient increases in serum AST [SGOT] or alkaline phosphatase concentration) have reportedly occurred during amiloride use; however, a causal relationship to the drug has not been established.

Nervous System Effects

Headache reportedly occurs in 3-8% of patients receiving amiloride. Adverse nervous system effects of amiloride, occurring in about 1-3% of patients, include weakness, fatigue, dizziness, and encephalopathy. Paresthesia, tremors, vertigo, nervousness, confusion, insomnia, depression, and somnolence occur less frequently.

Hematologic Effects

Although a causal relationship to amiloride has not been established, eosinophilia, leukopenia, neutropenia, aplastic anemia, increased hematocrit, and a positive Coombs' test have occurred rarely in patients receiving the drug. Following combined therapy with amiloride and hydrochlorothiazide, one fatality from agranulocytosis has been reported; however, the patient was also receiving other drugs, and a causal relationship to the diuretics has not been established.

Ocular, Otic, and Nasal Effects

Amiloride has caused visual disturbances and increased intraocular pressure in 1% or less of patients. Tinnitus and nasal congestion have also occurred rarely.

Other Adverse Effects

Respiratory symptoms occur occasionally during amiloride therapy and include cough and dyspnea. Shortness of breath occurs rarely. Erythematous rash, pruritus, alopecia, dryness of the mouth, taste alteration, and thirst reportedly occur in 1% or less of patients receiving amiloride; rash has been reported in 3-8% and pruritus in about 1-3% of patients receiving amiloride and hydrochlorothiazide. Photosensitivity reactions have occurred occasionally in patients receiving combined therapy with amiloride and hydrochlorothiazide, but this adverse effect has been associated with hydrochlorothiazide.

Muscle cramps occur in about 1-3% of patients receiving amiloride. Pain in the chest, back, joints, or extremities or aching of the leg, neck, or shoulder occur rarely.

Symptoms of the urogenital tract, such as polyuria, dysuria, urinary frequency, or bladder spasms, have occurred in about 1-3% of patients receiving amiloride. Mild proteinuria and transient glycosuria occur rarely. Gynecomastia has been reported in 1% or less of patients receiving with amiloride.101

Precautions and Contraindications

The potassium-sparing effect of amiloride can cause hyperkalemia, which may result in life-threatening cardiac arrhythmias. Following administration of amiloride, hyperkalemia occurs more frequently in patients with renal insufficiency, diabetes mellitus (with or without renal insufficiency), or in geriatric patients. Careful monitoring of serum potassium concentrations is necessary in all patients receiving amiloride, especially during initiation of therapy, after dosage adjustment, or during illness that could affect renal function. Amiloride should be used with caution in patients with impaired renal function (BUN concentration greater than 30 mg/dL or serum creatinine concentration greater than 1.5 mg/dL), since these patients are at particular risk of developing hyperkalemia. If amiloride is used in patients with impaired renal function, serum electrolyte, creatinine, and BUN determinations should be performed periodically (see Cautions: Hyperkalemia); some clinicians recommend weekly determinations during initiation of therapy in these patients.

Geriatric patients may be at particular risk of developing diuretic-induced hyponatremia and amiloride should be used with caution in these patients. Amiloride in combination with another diuretic should be used cautiously in debilitated patients, such as those who have hepatic cirrhosis with ascites and metabolic alkalosis or those who have resistant edema, since these patients are at particular risk of developing increased BUN concentrations, especially during vigorous diuresis. When amiloride is administered with other diuretics to these patients at risk, careful monitoring of serum electrolyte and BUN concentrations is recommended.

Amiloride should be used with caution in patients with severe, preexisting hepatic insufficiency, since they may develop hepatic encephalopathy during therapy with the drug. These patients should be carefully monitored for signs and symptoms of hepatic encephalopathy during amiloride therapy. (See Cautions: Hepatic Effects.)

Amiloride should be used with caution in debilitated patients, such as those with cardiopulmonary disease or uncontrolled diabetes mellitus, since these patients may be at particular risk of developing respiratory or metabolic acidosis; rapid increases in serum potassium concentrations may occur. Periodic, frequent monitoring of acid-base balance is necessary in these patients.

Whenever possible, use of amiloride should be avoided in diabetic patients, since these patients may be at particular risk of developing hyperkalemia during therapy with the drug; however, the drug has been used safely in diet-controlled diabetic patients with normal renal function. When amiloride is administered to diabetic patients, serum electrolyte determinations and renal function tests should be performed at regular intervals.

Amiloride is contraindicated in patients with serum potassium concentration greater than 5.5 mEq/L. The drug is also contraindicated in patients receiving other potassium-sparing diuretics such as spironolactone or triamterene, since rapid increases in serum potassium concentration may occur. Potassium supplementation or increased dietary intake of potassium (including use of potassium-containing salt substitutes) is contraindicated during amiloride therapy except when the patient has severe and/or refractory hypokalemia. If potassium supplementation is used with amiloride, careful monitoring of serum potassium concentration is necessary.

Amiloride is contraindicated in patients with anuria, acute or chronic renal insufficiency, or diabetic nephropathy. Amiloride therapy is also contraindicated in patients who are hypersensitive to the drug.

Pediatric Precautions

Safety and efficacy of amiloride in children, alone or in combination with hydrochlorothiazide, have not been established. Some clinicians have administered amiloride and hydrochlorothiazide concomitantly to children younger than 5 years of age with congenital heart disease. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Mutagenicity and Carcinogenicity

Amiloride did not produce mutagenic activity in various strains of Salmonella typhimurium when the Ames microbial mutagen assay was performed with or without metabolic activation. Following oral administration of the drug, no evidence of carcinogenicity was observed in rats or mice given daily doses up to 20 or 25 times the maximum daily human dose for 104 or 92 weeks, respectively.

Pregnancy, Fertility, and Lactation

Pregnancy

Amiloride has been shown to cross the placenta in animals. Following administration of a single 10-mg/kg oral dose of radiolabeled amiloride to rats, traces of drug crossed the placenta. Reproduction studies in rabbits and mice using oral amiloride doses up to 20 and 25 times the maximum daily human dose, respectively, have not revealed evidence of harm to the fetus. Reproduction studies in rats and rabbits using amiloride dosages up to 8 mg/kg daily have revealed evidence of reduced maternal growth rate in rats, maternal weight loss in rabbits, and adverse effects on growth and survival of rat offspring. There are no adequate and controlled studies to date using amiloride in pregnant women, and the drug should be used during pregnancy only when clearly needed.

Fertility

The effect of amiloride on fertility in humans is not known. Impotence and decreased libido have reportedly occurred in patients receiving the drug. Reproduction studies in rats using amiloride dosages up to 20 times the maximum daily dose in humans have not revealed evidence of impaired fertility.

Lactation

It is not known if amiloride is distributed into human milk; however, amiloride is distributed into the milk of lactating animals. Because of the potential for serious adverse reactions from amiloride in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Potassium-sparing Agents

Amiloride should not be used concurrently with another potassium-sparing agent (e.g., spironolactone, triamterene), since concomitant therapy with these drugs may increase the risk of hyperkalemia as compared with amiloride alone.

Potassium-sparing diuretics should be used with caution and serum potassium should be determined frequently in patients receiving an angiotensin-converting enzyme (ACE) inhibitor (e.g., captopril, enalapril), since concomitant administration with an ACE inhibitor may increase the risk of hyperkalemia. Dosage of amiloride should be reduced or the drug should be discontinued as necessary. Patients with renal impairment may be at increased risk of hyperkalemia.

Potassium-containing Preparations

Concurrent administration of amiloride with potassium supplements, potassium-containing medications (e.g., parenteral penicillin G potassium), or other substances containing potassium (e.g., salt substitutes, low-salt milk) may increase the risk of hyperkalemia as compared with amiloride therapy alone.

Hypotensive Agents

Although amiloride alone produces only a mild hypotensive effect, reduction in blood pressure may occur, especially when the drug is used with hypotensive agents. This effect is generally used to therapeutic advantage in antihypertensive therapy, but careful adjustment of dosage is necessary when amiloride is added to an antihypertensive regimen.

Nonsteroidal Anti-inflammatory Agents

In some patients receiving diuretics, including potassium-sparing diuretics, administration of a nonsteroidal anti-inflammatory agent (NSAIA) may decrease the diuretic, natriuretic, and hypotensive effects of the diuretic agent.101 When amiloride and a NSAIA are administered concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is attained.101 Since indomethacin and potassium-sparing diuretics, including amiloride, alone may be associated with increased serum potassium concentrations, the potential effects on potassium kinetics and renal function should be considered when the drugs are administered concomitantly.101

Lithium

Diuretics, including amiloride, generally should not be used concurrently with lithium since they reduce renal lithium clearance and may increase the risk of lithium toxicity. (See Lithium Salts 28:28.) However, amiloride has been used concomitantly with lithium to reduce lithium-induced polyuria† (secondary to lithium-induced nephrogenic diabetes insipidus) in a limited number of patients.100 Amiloride did not substantially affect plasma concentration, renal clearance, or urinary excretion of lithium in these patients, although a reduction in lithium dosage was necessary in one patient who had an asymptomatic increase in plasma lithium concentration (from 0.8 to 2 mEq/L) after initiation of amiloride therapy.100 Amiloride was effective in reducing lithium-induced polyuria in these patients, substantially decreasing urine output, with an associated increase in urine osmolality, while not substantially affecting plasma potassium or bicarbonate concentrations, urinary sodium excretion, or creatinine clearance.100 Amiloride also substantially increased urine osmolality following fluid deprivation and vasopressin administration in most patients.100 The beneficial effect of amiloride appeared to be maintained when amiloride dosage was decreased from 10 to 5 mg twice daily; within about 1 month after discontinuance of amiloride, polyuria recurred.100 Therefore, unlike thiazide diuretics which have also been used to reduce lithium-induced polyuria, amiloride does not appear to substantially affect lithium pharmacokinetics, although a reduction in lithium dosage may occasionally be necessary (e.g., in patients with amiloride-induced volume contraction and decreased glomerular filtration rate).100 If the drugs are used concomitantly, serum electrolyte and lithium concentrations, urine output, and serum and urine osmolality should be monitored and lithium dosage adjusted as necessary.100

Digoxin

Altered responses to digoxin therapy have occurred in patients receiving amiloride and digoxin concomitantly. In healthy individuals in one study, amiloride increased the renal clearance but decreased the extrarenal clearance of digoxin, resulting in slight increases in serum digoxin concentration. Inhibition of the positive inotropic effect of digoxin has also been observed in healthy individuals receiving amiloride. Patients receiving amiloride and digoxin concurrently should be carefully observed for altered responses to digoxin therapy. Further studies are needed to determine the clinical importance of the potential drug interaction between amiloride and digoxin.

Laboratory Test Interferences

Short-term administration of amiloride has resulted in severe hyperkalemia in uncontrolled diabetic patients following IV glucose tolerance testing; decreases in serum potassium concentration usually occur following IV glucose administration to patients not receiving the drug. The mechanism for this adverse effect may involve changes in total body potassium concentration or in the distribution of potassium; extrarenal effects of amiloride on electrolyte transport in diabetic patients may also be responsible. Amiloride should be discontinued in patients with diabetes mellitus at least 3 days prior to glucose tolerance testing.

Acute Toxicity

There is no experience in humans with overdosage of amiloride.

Pathogenesis

Acute toxicity studies in animals established the oral LD₅₀ of amiloride (calculated as the base) as 56 mg/kg in mice and 36-86 mg/kg in rats depending on the strain.

Manifestations

Overdosage of amiloride would be expected to produce signs and symptoms that are mainly extensions of common adverse reactions such as dehydration and electrolyte disturbance.

Treatment

In the event of overdosage, amiloride should be discontinued and the patient should be carefully monitored. There is no specific antidote for amiloride overdosage. In acute amiloride overdosage, the stomach should be emptied by inducing emesis or by lavage. If the patient is comatose or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Supportive and symptomatic treatment should be initiated. It is not known if amiloride is dialyzable.

If severe hyperkalemia occurs (i.e., serum potassium concentration greater than 6.5 mEq/L), specific measures such as IV administration of sodium bicarbonate or oral or parenteral administration of glucose with a rapid-acting insulin preparation should be instituted to reduce serum potassium concentrations. If necessary, a cation exchange resin (e.g., sodium polystyrene sulfonate) may be administered orally or as a retention enema. Patients with persistent hyperkalemia may require dialysis.

Pharmacology

Amiloride exhibits potassium-sparing, natriuretic, diuretic, and hypotensive effects.

Renal Effects

Like triamterene, amiloride acts directly on the distal renal tubule of the nephron to inhibit sodium-potassium ion exchange. Although the exact mechanism(s) of action has not been fully elucidated, amiloride decreases sodium reabsorption in the distal tubule by inhibiting cellular sodium transport mechanisms such as the conductive sodium influx pathway and possibly the sodium-hydrogen ion exchange system. Amiloride's effects on sodium transport produce reductions in the transtubular electrical-potential difference resulting in inhibition of passive distal tubular potassium secretion. Amiloride apparently also inhibits hydrogen ion secretion. Unlike spironolactone, amiloride does not competitively inhibit aldosterone and its diuretic activity is independent of aldosterone. Amiloride does not inhibit carbonic anhydrase activity and has no effect on free water clearance or concentrating mechanisms.

Administration of amiloride increases urinary excretion of sodium, bicarbonate, and calcium with little, if any, increase in chloride excretion. Amiloride has less natriuretic activity than furosemide or thiazide diuretics, since a relatively small percentage of sodium reabsorption occurs in the distal tubule of the kidney where amiloride exerts its principal effect. Urinary excretion of potassium is usually decreased during amiloride therapy and may be associated with an increase in plasma potassium concentration. Decreased potassium excretion is most pronounced when amiloride is given with a kaliuretic diuretic. Concomitant administration of amiloride with a more potent natriuretic diuretic results in approximately additive effects of the drugs on urinary sodium excretion and an antagonistic effect on potassium excretion. Urinary excretion of magnesium also decreases during amiloride therapy. Amiloride decreases urinary excretion of hydrogen and increases bicarbonate excretion resulting in increased urinary pH. Amiloride's effects on electrolytes appear to be dose dependent up to a single oral dose of about 15 mg.

Following administration of amiloride, increased urinary aldosterone and plasma renin concentrations have occurred, probably as a compensatory feedback mechanism caused by potassium retention and natriuresis.

Unlike thiazide diuretics, amiloride does not consistently inhibit the excretion of uric acid, and variable effects on serum uric acid concentration have been observed. Although amiloride alone decreased serum uric acid concentration in hypertensive patients in 2 studies, the drug did not prevent hydrochlorothiazide-induced hyperuricemia when these diuretics were used concomitantly. In another study, amiloride appeared to reduce the elevation of serum uric acid concentration produced by thiazide diuretics. Further studies are needed to determine the extent of uricosuric activity of amiloride.

Following administration of amiloride, transient increases in BUN and serum creatinine concentrations have been reported; however, glomerular filtration rate and renal blood flow have remained relatively unchanged. (See Cautions: Renal Effects.)

Metabolic Effects

Limited evidence in animals suggests that amiloride can alter glucose metabolism; the drug has increased insulin release and serum concentration and decreased blood glucose concentration in mice. Amiloride does not appear to be diabetogenic or to alter carbohydrate metabolism in humans. In one study in hypertensive patients, impaired glucose tolerance returned to normal following substitution of amiloride for thiazide diuretics. Diabetic patients may be predisposed to amiloride-induced hyperkalemia. (See Cautions: Precautions and Contraindications.)

Amiloride's effects on urinary electrolyte excretion can result in alterations in acid-base balance; metabolic acidosis may occur. Metabolic acidosis may potentiate the hyperkalemic effect of amiloride by causing an efflux of potassium from cells. (See Cautions: Metabolic Effects.)

In vitro studies have shown that amiloride inhibits protein synthesis. Amiloride appears to block sodium influx which is necessary to initiate cell growth.

Cardiovascular Effects

Amiloride alone produces mild diuresis and the drug has some hypotensive activity. Following administration of amiloride to hypertensive patients, reductions of about 10-20 mm Hg for systolic and 5-10 mm Hg for diastolic blood pressures have occurred. Amiloride is most often used in combination with a thiazide diuretic for the treatment of hypertension. In several comparative studies, combined therapy with amiloride and hydrochlorothiazide resulted in hypotensive effects greater than those of amiloride therapy alone.

The potassium-sparing effect of amiloride may result in hyperkalemia in susceptible patients (i.e., those with renal insufficiency or diabetes mellitus, or geriatric patients) which may produce ECG abnormalities and life-threatening cardiac arrhythmias. (See Cautions: Precautions and Contraindications.)

Pharmacokinetics

Absorption

Following oral administration, about 50% of a dose of amiloride is absorbed. Food decreases the extent of GI absorption to about 30% of an administered dose of the drug, but does not affect the rate of absorption.

The onset of diuretic activity of amiloride usually occurs within 2 hours following oral administration of the drug. In healthy, fasting adults, peak plasma concentrations of approximately 38-48 ng/mL are reached 3-4 hours after a 20-mg oral dose of amiloride. Following oral administration of a single dose, amiloride's effect on urinary electrolyte excretion peaks within 6-10 hours and persists for about 24 hours.

Plasma concentrations of amiloride required for therapeutic effects have not been established.

Distribution

The apparent volume of distribution for amiloride has been calculated to be 350-380 L, which suggests a large extravascular distribution of the drug. The extent of protein binding of amiloride has not been determined to date.

Although it is not known if amiloride crosses the placenta in humans, the drug crosses the placenta in animals. Amiloride is distributed into the milk of lactating animals, but it is not known if amiloride is distributed into human milk.

Elimination

Based on limited data, the half-life of amiloride has been reported to vary from 6-9 hours following single-dose administration in patients with normal renal function; however, it has been suggested that the terminal half-life for amiloride may be longer. Following oral administration in one study in patients with impaired renal function (i.e., creatinine clearance ranging from 5-46 mL/minute), the half-life of amiloride in the terminal phase ranged from 21-144 hours.

Amiloride is eliminated mainly via urinary excretion of unmetabolized drug. About 50% of a 20-mg oral dose of amiloride is excreted unchanged in urine within 72 hours, and about 40% is excreted in feces within 72 hours, probably as unabsorbed drug. Fecal concentrations of amiloride may also represent biliary elimination of the drug. Although the extent of biliary elimination in humans has not been determined, following administration of a 1 mg/kg IV dose of amiloride in dogs, less than 2% of the dose was distributed into bile over 4 hours.

Chemistry and Stability

Chemistry

Amiloride hydrochloride is a pyrazinecarbonyl-guanidine-derivative, potassium-sparing diuretic. Amiloride is chemically unrelated to other known diuretics but has some structural similarities to triamterene, with the presence of an amino-substituted pyrazine ring structure and 3 amino radicals. Amiloride hydrochloride occurs as a dihydrate, yellow to greenish-yellow, crystalline powder, and has solubilities of 5.2 mg/mL in water and 19.6 mg/mL in alcohol at 25°C. Dosage and potency of amiloride hydrochloride are calculated on the dried basis. The drug has a pK_a of 8.7.

Stability

Amiloride hydrochloride tablets should be stored in well-closed containers at a temperature less than 40°C, preferably between 15-30°C; freezing of the tablets should be avoided.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

100. Battle DC, von Riotte AB, Gaviria M et al. Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N Engl J Med . 1985; 312:408-14. [PubMed 3969096]

101. Merck & Co. Midamor^® (amiloride hydrochloride) tablets prescribing information. West Point, PA; 1992 Apr.

103. Anon. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Part II. Management of heart failure: approaches to the prevention of heart failure. Am J Cardiol . 1999; 83:9-38A.

104. The Captopril-Digoxin Multicenter Research Group. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JAMA . 1988; 259:539-44. [PubMed 2447297]

105. Richardson A, Bayliss J, Scriven AJ et al. Double-blind comparison of captopril alone against frusemide plus amiloride in mild heart failure. Lancet . 1987; 2:709-11. [PubMed 2888942]

106. Sherman LG, Liang CS, Baumgardner S et al. Piretanide, a potent diuretic with potassium-sparing properties, for the treatment of congestive heart failure. Clin Pharmacol Ther . 1986; 40:587-94. [PubMed 3533372]

107. Patterson JH, Adams KF Jr, Applefeld MM et al. Oral torsemide in patients with chronic congestive heart failure: effects on body weight, edema, and electrolyte excretion. Pharmacotherapy . 1994; 14:514-21. [PubMed 7997385]

108. Wilson JR, Reichek N, Dunkman WB et al. Effect of diuresis on the performance of the failing left ventricle in man. Am J Med . 1981;70:234-9. [PubMed 7468610]

109. Parker JO. The effects of oral ibopamine in patients with mild heart failure—a double blind placebo controlled comparison to furosemide. Int J Cardiol . 1993; 40:221-7. [PubMed 8225657]

111. National high blood pressure education program working group on hypertension control in children and adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics . 2004; 114(Suppl 2):555-76. [PubMed 15286277]

500. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). Bethesda, MD: National Institutes of Health; 2004 Aug. (NIH publication No. 04-5230.)

501. James PA, Oparil S, Carter BL et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA . 2014; 311:507-20. [PubMed 24352797]

502. Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens . 2013; 31:1281-357. [PubMed 23817082]

503. Go AS, Bauman MA, Coleman King SM et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension . 2014; 63:878-85. [PubMed 24243703]

504. Weber MA, Schiffrin EL, White WB et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich) . 2014; 16:14-26. [PubMed 24341872]

505. Wright JT, Fine LJ, Lackland DT et al. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med . 2014; 160:499-503. [PubMed 24424788]

506. Mitka M. Groups spar over new hypertension guidelines. JAMA . 2014; 311:663-4. [PubMed 24549531]

507. Peterson ED, Gaziano JM, Greenland P. Recommendations for treating hypertension: what are the right goals and purposes?. JAMA . 2014; 311:474-6. [PubMed 24352710]

508. Bauchner H, Fontanarosa PB, Golub RM. Updated guidelines for management of high blood pressure: recommendations, review, and responsibility. JAMA . 2014; 311:477-8. [PubMed 24352759]

515. Thomas G, Shishehbor M, Brill D et al. New hypertension guidelines: one size fits most?. Cleve Clin J Med . 2014; 81:178-88. [PubMed 24591473]

523. Fihn SD, Gardin JM, Abrams J et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation . 2012; 126:e354-471.

524. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation . 2013; 128:e240-327.

526. Kernan WN, Ovbiagele B, Black HR et al. Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke . 2014; :. [PubMed 24788967]

530. Myers MG, Tobe SW. A Canadian perspective on the Eighth Joint National Committee (JNC 8) hypertension guidelines. J Clin Hypertens (Greenwich) . 2014; 16:246-8. [PubMed 24641124]

536. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl . 2012: 2: 337-414.

700. Yancy CW, Jessup M, Bozkurt B et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation . 2016; :.

713. Gupta D, Georgiopoulou VV, Kalogeropoulos AP et al. Dietary sodium intake in heart failure. Circulation . 2012; 126:479-85. [PubMed 22825409]

723. Hummel SL, Konerman MC. Dietary Sodium Restriction in Heart Failure: A Recommendation Worth its Salt?. JACC Heart Fail . 2016; 4:36-8. [PubMed 26738950]

724. Yancy CW. The Uncertainty of Sodium Restriction in Heart Failure: We Can Do Better Than This. JACC Heart Fail . 2016; 4:39-41. [PubMed 26738951]

1200. Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension . 2018; 71:el13-e115. [PubMed 29133356]

1201. Bakris G, Sorrentino M. Redefining hypertension - assessing the new blood-pressure guidelines. N Engl J Med . 2018; 378:497-499. [PubMed 29341841]

1202. Carey RM, Whelton PK, 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association hypertension guideline. Ann Intern Med . 2018; 168:351-358. [PubMed 29357392]

1207. Burnier M, Oparil S, Narkiewicz K et al. New 2017 American Heart Association and American College of Cardiology guideline for hypertension in the adults: major paradigm shifts, but will they help to fight against the hypertension disease burden?. Blood Press . 2018; 27:62-65. [PubMed 29447001]

1209. Qaseem A, Wilt TJ, Rich R et al. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med . 2017; 166:430-437. [PubMed 28135725]

1210. SPRINT Research Group, Wright JT, Williamson JD et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med . 2015; 373:2103-16. [PubMed 26551272]

1216. Taler SJ. Initial treatment of hypertension. N Engl J Med . 2018; 378:636-644. [PubMed 29443671]

1220. Cifu AS, Davis AM. Prevention, detection, evaluation, and management of high blood pressure in adults. JAMA . 2017; 318:2132-2134. [PubMed 29159416]

1222. Bell KJL, Doust J, Glasziou P. Incremental benefits and harms of the 2017 American College of Cardiology/American Heart Association high blood pressure guideline. JAMA Intern Med . 2018; 178:755-7. [PubMed 29710197]

1223. LeFevre M. ACC/AHA hypertension guideline: what is new? what do we do?. Am Fam Physician . 2018; 97(6):372-3. [PubMed 29671534]

1224. Brett AS. New hypertension guideline is released. From NEJM Journal Watch website. Accessed 2018 Jun 18. [Web]

1229. Ioannidis JPA. Diagnosis and treatment of hypertension in the 2017 ACC/AHA guidelines and in the real world. JAMA . 2018; 319(2):115-6. [PubMed 29242891]