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.
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 range; in 2 patients who developed hypokalemia at this dosage, 40 mg of amiloride daily was required.
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. 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). 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. 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.
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. 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. 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.
Most experts state that loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, torsemide) are the diuretics of choice for most patients with heart failure.
Amiloride has been used in the management of hypertension; however, other antihypertensive drugs (i.e., ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, thiazide diuretics) generally are preferred because of their established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes). 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. Potassium-sparing diuretics should be avoided in patients with renal insufficiency and in those with hyperkalemia (e.g., serum potassium concentrations exceeding 5 mEq/L while not receiving drug therapy).
Although comparative studies have not been performed to date, 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.
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.
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).
(See Drug Interactions: Lithium.)