EDECRIN®, SODIUM EDECRIN®
Ethacrynic Acid, Ethacrynate Sodium
Action and Clinical Pharmacology:
Ethacrynic acid is a saluretic-diuretic agent with marked potency and rapid onset of action. It is chemically unrelated to other diuretics. Patients with congestive heart failure (including acute pulmonary edema), renal edema, hepatic cirrhosis with ascites, and other conditions involving fluid retention have responded well to ethacrynic acid.
Ethacrynic acid has the following major characteristics:
Water and electrolyte excretion may be increased several times over that observed with thiazide diuretics. The urinary output is usually dose-dependent and related to the magnitude of fluid accumulation.
Electrolyte excretion pattern differs from that of thiazides. Initially, sodium and chloride excretion is usually substantial, and chloride loss exceeds that of sodium. With prolonged therapy, chloride excretion declines, and potassium and hydrogen ion excretion may increase. In patients with increased diuresis excessive amounts of potassium may be excreted. Ethacrynic acid is effective whether or not there is clinical acidosis or alkalosis.
Rapid onset of action usually is observed within 30 minutes after an oral dose or within 5 minutes after an i.v. injection.
Duration of action is moderate following oral administration (6 to 8 hours). The peak diuretic-saluretic activity occurs in about 2 hours.
Sulfhydryl binding propensity differs in certain respects from that of the organomercurials. Its mode of action is not by carbonic anhydrase inhibition.
Multiple sites of action. Ethacrynic acid acts on the proximal and distal portions of the tubule, and also on the ascending limb of the loop of Henle.
Indications And Clinical Uses:
Especially useful in patients unresponsive to the commonly used diuretics.
It has been found useful in the following conditions: congestive heart failure, acute pulmonary edema, renal edema (nephrotic syndrome), hepatic cirrhosis with ascites.
The majority of patients studied to date have been resistant in some degree to other diuretic agents; the remaining patients received ethacrynic acid as their first diuretic in the treatment of edema or were placed on the drug for comparative evaluations.
Experience to date with the use of ethacrynic acid for oral maintenance therapy has been limited. The duration of studies has varied from short-term investigations to continuous therapy of 1 year or longer.
Patients with chronic congestive heart failure many of whom were unresponsive to other diuretics, have responded successfully to short- or long-term therapy. These include patients with arteriosclerotic heart disease, rheumatic heart disease, hypertensive cardiovascular disease, pulmonary heart disease, and congenital heart disease. Long-term studies in patients who have received ethacrynic acid for over 6 months have been in patients with cardiac edema secondary to arteriosclerotic or valvular heart disease. The average duration of these studies has been about 9 months.
Patients with acute pulmonary edema have responded rapidly to the i.v. use of ethacrynate sodium. Clinical improvement is coincidental with the large increases in water and electrolyte excretion usually observed to begin within 5 minutes after injection. Ethacrynate sodium offers advantages over other diuretics because of its rapid action and effectiveness.
Ethacrynic acid is indicated for patients with the nephrotic syndrome. The greatest experience with this agent in renal edema has been in patients with the nephrotic syndrome. Use of the drug in these patients usually has been of short duration, ranging from 1 to 3 months, with treatment usually being initiated in the hospital.
Saluresis and diuresis may be achieved in patients unresponsive to other diuretics. Patients whose response to other diuretics has been suboptimal may obtain a greater effect from ethacrynic acid.
As with other diuretics, hypoproteinemia may reduce responsiveness to ethacrynic acid and the use of salt-poor albumin should be considered. In some patients, larger doses may be necessary to produce effective diuresis in renal than in cardiac edema. Ethacrynic acid is effective in many patients who have significant degrees of renal insufficiency. It has little or no effect on renal blood flow except following pronounced reduction in plasma volume when associated with rapid diuresis. The extreme sensitivity of patients with chronic renal failure to alterations in fluid or electrolyte balance dictates careful clinical and laboratory observation when diuretics are used, and these agents must be discontinued immediately if further deterioration in renal function occurs.
For reasons given below, initiation of diuretic therapy with ethacrynic acid in the cirrhotic patient with ascites is best carried out in the hospital. When maintenance therapy has been established, the individual can be satisfactorily followed as an outpatient.
Ethacrynic acid is usually effective in patients with cirrhosis who have ascites. Most studies have been of 3Â months’ duration, or less. Diuresis and saluresis have occurred in previously unresponsive patients. However, cirrhotic patients tolerate poorly acute shifts in electrolyte balance, and potassium excretion is often augmented as a result of associated aldosteronism. Therefore, careful clinical and laboratory observation is essential to avoid serious loss of potassium and chloride ions and the development of metabolic alkalosis, with resultant hepatic encephalopathy. These effects may be minimized by appropriate adjustment of dosage and by the use of supplemental potassium as the chloride with or without a potassium-sparing agent (see Dosage).
A variety of other edematous states have been successfully treated with ethacrynic acid; most of the experience has been of short duration. These include ascites due to malignancy, idiopathic edema, and lymphedema.
Children: Ethacrynic acid has been found useful in patients of the pediatric age group with the nephrotic syndrome. This experience has been mostly of short duration, in hospitalized patients resistant to other therapy. Pediatric patients with congenital heart disease also have responded to this agent. Information in infants is insufficient to recommend therapy with ethacrynic acid.
All diuretics, including ethacrynic acid, are contraindicated in anuria. If increasing azotemia and/or oliguria occur during treatment of severe, progressive renal disease, the diuretic should be discontinued.
Until further experience in infants is accumulated, therapy with oral and parenteral ethacrynic acid is contraindicated.
See also Warnings, Pregnancy and Lactation.
Hypersensitivity to any component of this product.
Warnings in Clinical States:
Ethacrynic acid is a potent and rapidly-acting diuretic that may lead to excessive diuresis and natriuresis with water depletion and electrolyte imbalance, which may result in hypokalemia or hypochloremic alkalosis with potassium depletion, hydrogen ion loss and extracellular fluid space contraction. This may occur in patients with marked fluid accumulation or when excessive doses are used but these adverse effects may also be encountered in patients with moderate degrees of edema. The safe use of potent diuretics requires careful understanding of their pharmacologic actions and in particular of the mechanisms of development of electrolyte imbalance. Close attention should be given to the directions of use and to identification of the individual patient response to the drug.
Frequent serum electrolyte, CO 2, and BUN determinations should be performed early in therapy and periodically thereafter during active diuresis. Baseline determination of electrolytes and renal function before therapy is recommended when pre-existing derangements are suspected. Any electrolyte abnormalities should be corrected or the drug temporarily withdrawn.
Ethacrynic acid should be given with caution to patients with advanced cirrhosis of the liver, particularly those with a history of previous episodes of electrolyte imbalance of hepatic encephalopathy. Like other diuretics it may precipitate hepatic coma and death.
Too vigorous a diuresis, as evidenced by rapid and excessive weight loss, may induce an acute hypotensive episode. In elderly cardiac patients, rapid contraction of plasma volume and the resultant hemoconcentration should be avoided to prevent the development of thromboembolic episodes such as cerebrovascular thromboses and pulmonary emboli which may be fatal. In patients receiving digitalis glycosides, excessive loss of potassium may precipitate digitalis toxicity. Care should also be exercised in patients receiving potassium-depleting steroids.
The effects of ethacrynic acid on electrolytes are related to its renal pharmacologic activity and are dose-dependent. The possibility of profound electrolyte and water loss may be avoided by weighing the patient throughout the treatment period, by monitoring electrolyte changes, by careful adjustment of dosage, by initiating treatment with small doses, and by using the drug on an intermittent schedule when possible. When excessive diuresis occurs, the drug should be withdrawn until homeostasis is restored. When excessive electrolyte loss occurs, the dosage should be reduced or the drug temporarily withdrawn, and if necessary judicious repletion of losses should be considered.
Avoidance of potassium depletion may be possible by adequate dietary supplementation, intermittent therapy, and when possible by careful liberalization of salt intake. Supplementary potassium chloride may however be required, particularly in cirrhosis or patients with a pre-existing degree of aldosteronism.
While potassium supplements may be indicated there have been numerous reports, published and unpublished, concerning nonspecific small bowel lesions, consisting of stenosis with or without ulceration, associated with administration of enteric-coated potassium salts alone or with oral diuretics. Surgery was frequently required and deaths have occurred.
Pregnancy: Not recommended for use in pregnant patients. Use of the drug in women of the childbearing age requires that its potential benefits be weighed against the possible hazards to the fetus. The safety and efficacy of the drug in toxemia of pregnancy have not been established.
Lactation: Contraindicated in nursing mothers. If use of the drug is deemed essential, the patient should stop nursing.
PrecautionsGeneral: Weakness, muscle cramps, paresthesias, thirst, anorexia, and signs of hyponatremia, hypokalemia, and/or hypochloremic alkalosis may occur following vigorous or excessive diuresis and these may be accentuated by rigid salt restriction. Rarely tetany has been reported following vigorous diuresis. During therapy with ethacrynic acid, liberalization of salt intake and supplementary potassium chloride are often necessary.
When metabolic alkalosis may be anticipated, e.g., in cirrhosis with ascites, the use of potassium chloride with or without a potassium-sparing agent before and continuously during therapy with ethacrynic acid may mitigate or prevent the hypokalemia. If a potassium-sparing agent is used, continued monitoring of electrolytes is still required because of the possible occurrence in this case of hyperkalemia.
In a few patients this diuretic has produced severe, watery diarrhea. If this occurs, it should be discontinued and not readministered.
Ethacrynic acid has little or no effect on glomerular filtration or on renal blood flow, except following pronounced reductions in plasma volume when associated with rapid diuresis. A transient increase in serum urea nitrogen may occur. This is usually reversible when the drug is discontinued.
Deafness, tinnitus and vertigo with a sense of fullness in the ears have occurred most frequently in patients with severe impairment of renal function. These symptoms have been associated most often with i.v. administration and with doses in excess of those recommended. The deafness has usually been reversible and of short duration (1 to 24 hours). However, in some critically ill patients the hearing loss has been permanent. A number of these patients were also receiving drugs known to be ototoxic.
Antihypertensive Agents: The safety and efficacy of ethacrynic acid in hypertension have not been established. However, the dosage of coadministered antihypertensive agents may require adjustment.
Orthostatic hypotension may occur in patients receiving antihypertensive agents when given ethacrynic acid.
Antibiotics: Ethacrynic acid may increase the ototoxic potential of other drugs such as aminoglycoside antibiotics. Their concurrent use should be avoided.
Warfarin: A number of drugs, including ethacrynic acid, have been shown to displace warfarin from plasma protein; a reduction in the usual anticoagulant dosage may be required in patients receiving both drugs.
Lithium: Lithium should generally not be given to patients receiving diuretics, since diuretics reduce renal clearance of lithium making the risk of lithium toxicity very high in such patients.
Corticosteroids: Ethacrynic acid may increase the risk of gastric hemorrhage associated with corticosteroid treatment.
Patients With Special Diseases and Conditions: Patients with refractory edema or having pre-existing degrees of aldosteronism and those receiving potassium depleting steroids are more likely to develop hypokalemia. This may be responsible for increased digitalis toxicity or result in hepatic coma in patients with advanced liver disease. These patients may therefore require potassium supplementation.
Gastrointestinal: anorexia, malaise, abdominal discomfort or pain, dysphagia, nausea, vomiting, and diarrhea. In a few patients, watery, profuse diarrhea, gastrointestinal bleeding, and acute pancreatitis has been reported.
Metabolic: Reversible hyperuricemia, decreased urinary urate excretion, and hyperglycemia have been reported. Acute gout has been precipitated. Rarely acute symptomatic hypoglycemia with convulsions, jaundice and abnormal tests of hepatocellular function have been reported.
Hematologic: Agranulocytosis, severe neutropenia, thrombocytopenia, and Henoch-Schönlein have been reported rarely.
Special Senses: Vertigo, deafness, and tinnitus, with a sense of fullness in the ears and blurred vision have occurred (see Precautions).
CNS: fatigue, apprehension and confusion.
Other: skin rash, headache, fever, chills and hematuria.
Ethacrynate sodium occasionally has caused local irritation and pain, and a rare instance of local thrombophlebitis has been reported after its use.
A number of possibly drug-related deaths have occurred in critically ill patients refractory to other diuretics. These generally have fallen into two categories: (1) patients with severe myocardial disease who have been receiving digitalis and presumably developed acute hypokalemia with fatal arrhythmia; (2) patients with severely decompensated hepatic cirrhosis with ascites, with or without accompanying encephalopathy, who were in electrolyte imbalance and died because of intensification of the electrolyte defect.
Dosage And Administration:
Dosage must be regulated carefully to prevent a more rapid or substantial loss of fluid or electrolyte than is indicated or necessary. The magnitude of diuresis and natriuresis is largely dependent on the degree of fluid accumulation present in the patient. Similarly, the extent of potassium excretion is determined in large measure by the presence and magnitude of aldosteronism.
Oral: To Initiate Diuresis: Adults: The smallest dose required to produce gradual weight loss (about 0.5 to 1 kg/day) is recommended.
Onset of diuresis usually occurs at 50 to 100 mg for adults. After diuresis has been achieved, the minimally effective dose (usually from 50 to 200 mg daily) may be given on a continuous or intermittent dosage schedule. Dosage adjustments are usually in 25 to 50 mg increments to avoid derangement of water and electrolyte excretion.
The patient should be weighed under standard conditions before and during the institution of diuretic therapy with this compound. Small alterations in dose might prevent a massive diuretic response.
The following schedule may be helpful in determining the smallest effective dose. Day 1: 50 mg (single dose) after a meal. Day 2: 50 mg twice daily after meals, if necessary. Day 3: 100 mg in the morning and 50 to 100 mg following the afternoon or evening meal, depending upon response to the morning dose.
A few patients may require initial and maintenance doses as high as 200 mg twice daily. These higher doses, which should be achieved gradually, are most often required in patients with severe, refractory edema.
Children: In children, the initial dose should be 25 mg. Careful stepwise increments in dosage of 25 mg should be made to achieve effective maintenance. A dosage for infants has not been established.
Maintenance Therapy: It is usually possible to reduce the dosage and frequency of administration once dry weight has been achieved.
Ethacrynic acid may be given intermittently after an effective diuresis is obtained with the regimen outlined above. Dosage may be on an alternate daily schedule or more prolonged periods of diuretic therapy may be interspersed with rest periods. Such an intermittent dosage schedule allows time for correction of any electrolyte imbalance and may provide a more efficient diuretic response.
The chloruretic effect of this agent may give rise to retention of bicarbonate and metabolic alkalosis. This may be corrected by giving chloride (ammonium chloride or arginine chloride). Ammonium chloride should not be given to cirrhotic patients.
Ethacrynic acid has additive effects when used with other diuretics.
Small doses of ethacrynic acid may be added to existing diuretic regimens to maintain basal weight. This drug may potentiate the action of carbonic anhydrase inhibitors, with augmentation of natriuresis and kaliuresis. Therefore, when adding ethacrynic acid, the initial dose and changes of dose should be in 25 mg increments to avoid electrolyte depletion. Rarely, patients who failed to respond to ethacrynic acid have responded to older established agents.
While many patients do not require supplemental potassium, the use of potassium chloride or potassium-sparing agents or both, during treatment with ethacrynic acid is advisable, especially in cirrhotic or nephrotic patients and in patients receiving digitalis.
Salt liberalization usually prevents the development of hyponatremia and hypochloremia. During treatment with ethacrynic acid, salt may be liberalized to a greater extent than with other diuretics. Cirrhotic patients however, usually require at least moderate salt restriction concomitant with diuretic therapy.
I.V.: For i.v. use when oral intake is impractical or in urgent conditions, such as acute pulmonary edema.
Adults: The usual i.v. dose for the average sized adult is 50 mg, or 0.5 to 1.0 mg/kg of body weight. Usually only 1 dose has been necessary; occasionally a second dose at a new injection site, to avoid possible thrombophlebitis, may be required. A single i.v. dose not exceeding 100 mg has been used in critical situations. Children: Insufficient pediatric experience precludes recommendation for this age group.
The solution may be given slowly through the tubing of a running infusion or by direct i.v. injection over a period of several minutes.
Ethacrynate sodium should not be given s.c. or i.m. because of local pain and irritation.
To reconstitute the dry material, add 50 mL of 5% Dextrose Injection or Sodium Chloride Injection to the vial. Occasionally, some 5% Dextrose Injection solutions may have a low pH (below 5). The resulting solution with such a diluent may be hazy or opalescent. I.V. use of such a solution is not recommended.
Do not mix this solution with whole blood or its derivatives. Because there is no preservative contained in the vial, a fresh solution should be prepared just prior to each administration. Any unused solution should be discarded.
Availability And Storage:
Edecrin: Each white, scored tablet, with the MSD symbol on one side, contains: ethacrynic acid 50 mg. Nonmedicinal ingredients: colloidal silicon dioxide, cornstarch, lactose, magnesium stearate and talc. Gluten- and tartrazine-free. Bottles of 50.
Sodium Edecrin: Each vial of dry white material either in a plug form or as a powder, contains: ethacrynate sodium equivalent to ethacrynic acid 50 mg. Nonmedicinal ingredients: mannitol.
EDECRIN®, SODIUM EDECRIN® Merck Frosst Ethacrynic Acid Ethacrynate Sodium Diuretic-Saluretic