Ethacrynic acid is used in the management of edema associated with heart failure, nephrotic syndrome, and hepatic cirrhosis. IV ethacrynate sodium may be used as an adjunct in the treatment of acute pulmonary edema.
Careful etiologic diagnosis should precede the use of any diuretic. Because the potent diuretic effect of ethacrynic acid may result in severe electrolyte imbalance and excessive fluid loss, hospitalization of the patient during initiation of therapy is advisable, especially for patients with hepatic cirrhosis and ascites or chronic renal failure. In prolonged diuretic therapy, intermittent use of the drug for only a few days each week may be advisable. Ethacrynic acid may be administered cautiously for additive effect with most other diuretics; however, since ethacrynic acid and other loop diuretics (e.g., furosemide) act in a similar manner, there is no rationale for using these drugs together.
Ethacrynic acid is used 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.
Diuretics increase urinary sodium excretion and decrease physical signs of fluid retention in patients with heart failure. Results of short-term studies in patients with heart failure indicate that diuretic therapy is associated with a reduction in jugular venous pressures, pulmonary congestion, ascites, peripheral edema, and body weight within a few days of initiating such therapy. In addition, diuretics may improve cardiac function, symptoms, and exercise tolerance in these patients. However, since there are no long-term studies of diuretic therapy in patients with heart failure, the effects of diuretics on morbidity and mortality are not known. Nevertheless, most long-term studies of therapeutic interventions for heart failure have been in patients receiving diuretic therapy. Diuretics should not be used as monotherapy in patients with heart failure even if symptoms of heart failure (e.g., peripheral edema, pulmonary congestion) are well controlled, because diuretics alone do not prevent progression of heart failure.
Depending on the dosage employed, diuretics may alter the efficacy and safety of concomitantly used drugs in heart failure, and therefore diuretic dosage should be selected carefully. Excessive diuretic dosages may lead to volume depletion, which can increase the risk of hypotension in patients receiving ACE inhibitors or vasodilators and renal insufficiency in patients receiving ACE inhibitors or angiotensin II receptor antagonists. Inadequate diuretic dosages may lead to fluid retention, which can decrease the response to ACE inhibitors and increase the risk of β-blocker therapy. Patients with mild heart failure may respond favorably to low doses of diuretics, since absorption of diuretics from the GI tract is rapid and the drugs are distributed rapidly to the renal tubules in such patients; however, as heart failure advances, absorption of the drugs may be delayed because of bowel edema or intestinal hypoperfusion, and distribution may be impaired because of decreases in renal perfusion and function. Therefore, dosage of diuretics usually needs to be increased with progression of heart failure; eventually, patients may become resistant to even high dosages of diuretics. If resistance to diuretics occurs, IV administration of a diuretic or concomitant use of 2 or more diuretics (e.g., a loop diuretic and metolazone, a loop diuretic and a thiazide diuretic) may be necessary; alternatively, short-term administration of a drug that increases blood flow (e.g., a positive inotropic agent such as dopamine) may be necessary. ACCF and AHA state that IV loop diuretics should be administered promptly to all hospitalized heart failure patients with substantial fluid overload to reduce morbidity. In addition, ACCF and AHA state that low-dose dopamine infusions may be considered in combination with loop diuretics to augment diuresis and preserve renal function and renal blood flow in patients with acute decompensated heart failure, although data are conflicting and additional study and experience are needed.
Most experts state that loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, torsemide) are the diuretics of choice for most patients with heart failure, especially those with renal impairment or substantial fluid retention, since loop diuretics increase sodium excretion to 20-25% of the filtered load of sodium, enhance free water clearance, and maintain their efficacy unless renal function is severely impaired (e.g., creatinine clearance less than 5 mL/minute). In contrast, thiazide diuretics increase fractional sodium excretion to only 5-10% of the filtered load, tend to decrease free water clearance, and lose their efficacy in patients with moderate renal impairment (e.g., creatinine clearance less than 30 mL/minute). However, thiazides may be preferred in some patients with concomitant hypertension because of their sustained antihypertensive effects. In patients who develop azotemia or hypotension before therapeutic goals are achieved, consideration to decreasing the rate of diuresis may be made, but diuretic therapy should continue until fluid retention is eliminated, provided that decreases in blood pressure remain asymptomatic; excessive concern about hypotension and azotemia may result in suboptimal diuretic therapy leading to refractory edema.
Once fluid retention has resolved in patients with heart failure, diuretic therapy should be maintained to prevent recurrence of fluid retention. Ideally, diuretic therapy should be adjusted according to changes in body weight (as an indicator of fluid retention) rather than maintained at a fixed dosage.
Ethacrynate sodium may be administered IV as an adjunct in the treatment of acute pulmonary edema; however, the drug should be used cautiously when acute pulmonary edema is a complication of cardiogenic shock associated with acute myocardial infarction because diuretic-induced hypovolemia may reduce cardiac output.
Ethacrynic acid also may be used cautiously in the management of edema associated with the nephrotic syndrome and in patients with hepatic cirrhosis, but such edema is frequently refractory to treatment. In patients with renal edema, hypoproteinemia may result in reduced responsiveness to ethacrynic acid and the administration of albumin human should be considered.
Ethacrynic acid also is indicated for short-term management of ascites caused by malignancy, idiopathic edema, or lymphedema and for short-term management of hospitalized pediatric patients with congenital heart disease or nephrotic syndrome. When metabolic alkalosis may be anticipated, a potassium-rich diet, potassium supplements, or potassium-sparing diuretics may be necessary before and during ethacrynic acid therapy to mitigate or prevent hypokalemia in cirrhotic, nephrotic, or digitalized patients.
(See Cautions: Electrolyte, Fluid, and Renal Effects.)
Ethacrynic acid has been used orally in the management of hypertension. However, the drug is not recommended in current hypertension management guidelines for this use; because of established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes), ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics generally are considered the preferred drugs for the initial management of hypertension in adults. When loop diuretics are indicated, other agents (e.g., furosemide, bumetanide, torsemide) generally are recommended. However, ethacrynic acid may still be considered when diuretic therapy is indicated in patients hypersensitive to sulfonamides (e.g., other loop diuretics, thiazides) because of the drug's nonsulfonamide structure. Although some clinicians have reported good results with 200-400 mg of ethacrynic acid daily, the incidence of adverse GI effects was high and heart rate was increased substantially in some patients.
IV ethacrynate sodium has been used as an adjunct to hypotensive agents in the management of hypertensive crises, especially when accompanied by pulmonary edema. In addition to producing rapid diuresis, ethacrynic acid enhances the hypotensive effects of other drugs and counteracts the sodium retention caused by some of these agents.
Ethacrynic acid has been used IV alone or with 0.9% sodium chloride injection to increase renal excretion of calcium in patients with hypercalcemia. The drug has also been used concomitantly with mannitol in the management of ethylene glycol poisoning and to increase bromide excretion in the management of bromide intoxication.
Ethacrynic acid has been used with success in the treatment of nephrogenic diabetes insipidus that is not responsive to vasopressin or chlorpropamide.