Administration Of Ethacrynic Acid Research Articles

Influence of extracellular volume expansion on the composition of proximal tubular fluid in man.

1. Distal blockade by simultaneous administration of ethacrynic acid and chlorothiazide was performed in healthy subjects whose extracellular fluid was expanded by iso-osmotic sodium chloride or bicarbonate. The results obtained were compared with those from non-expanded subjects (Ardaillou & Fillastre, 1969). 2. By this technique urine approximates in composition to proximal tubular fluid and may be used to provide information on its composition. As in other mammals, UNa/PNa and Uosm/Posm were close to 1, whatever the experimental conditions. UCl/PCl was always higher and UHCO3/PHCO3 always less than 1. 3. Extracellular fluid expansion with sodium chloride depresses water and sodium reabsorption as shown by the increase of tubular fluid and the diminution of UInul/PInul and TNa/GFR × PNa where TNa and GFR × PNa are respectively the amounts of sodium reabsorbed and filtered per min. It also decreases bicarbonate proximal Tm. The influence on bicarbonate reabsorption is more marked in alkali-loaded than in acid-loaded subjects. 4. Extracellular fluid expansion with iso-osmotic sodium bicarbonate also depresses water, sodium and bicarbonate reabsorption. These results suggest that chloride administration is not necessary to diminish bicarbonate reabsorption and that tubular reabsorption of bicarbonate depends in part on the state of effective extracellular volume.

Deafness Following Standard Intravenous Dose of Ethacrynic Acid

Two nonuremic patients experienced neurosensory hearing loss after the intravenous administration of standard doses of ethacrynic acid. Both were receiving nontoxic doses of aminoglycoside antibiotics concurrently. Total deafness occurred within 15 minutes of the administration of ethacrynic acid and was not accompanied by vertigo, nausea, or vomiting. The impairment of hearing was clearly transient in one patient. In the other patient, results of histologic examination of the inner ear at the time of autopsy were normal.

Ethacrynic acid and furosemide: Diuretic and hemodynamic effects and clinical uses

Ethacrynic acid and furosemide are the most potent diuretic agents currently available. Although the evidence for a proximal tubular site of action is conflicting, the main action of both agents is inhibition of sodium reabsorption along the ascending loop of Henle. Acute administration of ethacrynic acid and furosemide may produce a transient slight increase in both glomerular filtration rate and renal plasma flow, which is followed by a decrease in glomerular filtration rate and renal plasma flow with diuresis and dehydration. In patients who do not have congestive heart failure, acute administration of either drug results in a decrease in plasma volume, central venous pressure and cardiac index, and an increase in arteriovenous oxygen differences. In patients with severe congestive heart failure, plasma volume and central venous pressure fall, but cardiac index increases and arteriovenous oxygen difference narrows. Both drugs have rapid and short duration of diuretic action and wide and steep dose-response curves. Therefore, both drugs can be used in patients with mild to severe congestive heart failure or fluid retention. Both drugs are also effective despite the presence of hypoalbuminemia, acid-base and electrolyte imbalance and a low glomerular filtration rate. Therefore, refractoriness to either agent is unusual in the absence of severe renal failure. Neither drug has been widely used for antihypertensive therapy. No marked difference in antihypertensive potency from that of standard thiazide drugs has been noted. Both drugs are especially useful in those patients with severe hypertension who have concomitant renal failure or congestive heart failure. In this group of patients they help to maintain adequate urinary output and potentiate other antihypertensive drugs. Despite the potent diuretic action of both drugs, side effects are relatively infrequent. However, close monitoring of diuretic response, and acid-base and electrolyte status is recommended.

Hemodynamic effects of ethacrynic acid in patients with refractory acute left ventricular failure

Fourteen patients with acute left ventricular failure were studied in a coronary care unit. Cardiac output, heart rate, urinary flow, and aortic and pulmonary artery pressures were measured before and after intravenous administration of ethacrynic acid, 50 to 75 mg. Mean pulmonary artery systolic pressure decreased from 52.4 ± 15.3 to 38.5 ± 10.1 mm Hg (p < 0.01) and pulmonary artery diastolic pressure from 24.1 ± 7.71 to 15.5 ± 6.7 mm Hg (p < 0.01). Arterial mixed-venous oxygen content difference decreased from 6.37 ± 1.38 to 6.16 ± 1.92 volumes per cent while urinary flow increased from 54 ± 14 to 413 ± 213 ml/hour (p < 0.001). Oxygen consumption, heart rate, aortic pressure and cardiac output did not differ significantly from control values. All subjects showed clinical improvement, and no instance of hypotension, sepsis, arrhythmia or death occurred. Patients with acute heart failure appeared to operate on the flat portion of a depressed Starling's curve: the decreases in ventricular filling pressure were not associated with significant changes in stroke volume. The tendency for oxygen consumption and arterial mixed-venous oxygen content difference to fall was probably related to decreased respiratory work induced by pulmonary decongestion. Ethacrynic acid appears to be a safe, effective drug for patients with acute heart failure.

Electron microscopic study of the inner ear after ethacrynic acid intoxication.

The effects of ethacrynic acid, a potent new diuretic which causes sodium and potassium excretion, on the inner ear were studied by means of phase contrast microscopy and electron microscopy. High doses of ethacrynic acid were administered intra-peritoneally to mice until the Preyer’s reflex disappeared. Some of the animals were sacrificed immediately after final administration of ethacrynic acid and the others were allowed to recover for 1 to 4 months. The drug mainly affected the marginal cells of the stria vascularis. This structural change in the stria vascularis has recovered after 1 to 4 months. The organ of Corti was less affected than the stria vascularis but degeneration appeared in the outer hair cells in the lower turn, starting with degenerations in the mitochondria and distortion of stereocilia which did not recover. In the vestibule, vacuolization and protrusion of the supra-nuclear cytoplasm were observed in both the type I and type II hair cells. The nerve chalice was swollen and its membrane and the cytoplasmic membrane of the type I hair cell were irregularly separated. The ototoxic mechanism of this drug to the inner ear sensory epithelia and the transient hearing loss were discussed from the morphological point of view.

The interrelationship between ECF volume and ECF anion composition in the regulation of sodium excretion.

1. The interrelationship between extracellular fluid volume and extracellular anion composition as determinants of sodium excretion was studied in thirty-four dogs. In six, hypovolaemia, hypochloraemia and hyperbicarbonataemia were induced by the administration of ethacrynic acid and a low chloride diet. Isotonic sodium bicarbonate was then infused resulting in a progressive increase in sodium excretion. After 3 h while continuing the sodium bicarbonate infusion, an infusion of hydrochloric acid was given in order to return extracellular anion composition towards normal. This resulted in a prompt fall in sodium excretion without a change in GFR. 2. Ten studies were performed to determine whether this hydrochloric acid-induced enhancement of sodium conservation depends upon the presence of volume depletion and sodium avidity or whether it could also be demonstrated under circumstances of volume expansion. In these studies, hypervolaemia, hypochloraemia, hyperbicarbonataemia and a brisk natriuresis were induced by infusing isotonic sodium bicarbonate into normal dogs. The addition of hydrochloric acid returned anion composition to normal and, as before, resulted in a prompt suppression of sodium excretion despite continued sodium loading and enhanced glomerular filtration. 3. Results obtained from three related protocols (six animals each) confirmed that hypochloraemia and hyperbicarbonataemia were the necessary prerequisite conditions for this effect of hydrochloric acid in volume expanded animals. We interpret these findings as evidence that the response of the kidney to changes in extracellular fluid volume may be significantly affected by changes in the extracellular concentration of physiologic anions.

Enhancement by potent diuretics of renal tubular necrosis induced by cephaloridine.

1. Administration of frusemide or ethacrynic acid to cephaloridine-treated mice increased both the incidence and extent of proximal renal tubular necrosis compared with that obtained in cephaloridine-treated control mice.2. Administration of frusemide to cephaloridine-treated rats produced significant changes in urine output, electrolyte excretion and proteinuria, and plasma urea nitrogen and creatinine values were significantly increased compared with controls or rats that received frusemide or cephaloridine alone.3. Histological examination of the kidneys showed a higher incidence and greater extent of tubular necrosis in rats that received both frusemide and cephaloridine.4. It is suggested that this adverse drug interaction may have contributed to the deterioration in renal function observed in some patients treated with diuretics and cephaloridine concurrently.

The effect of altered sodium concentration in the distal nephron segments on renin release.

Ethacrynic acid, a potent inhibitor of sodium reabsorption in the ascending limb of Henle's loop, produces a sharp rise in renal venous renin activity within 5 min after intravenous administration in anesthetized dogs. This response persists when volume depletion is prevented by returning urinary outflow to the femoral vein. Comparable studies with chlorothiazide, a diuretic with little or no effect on the medullary portion of the ascending limb of the loop of Henle, failed to produce a significant increase in renal venous renin activity.When administered during ureteral occlusion, ethacrynic acid produced no change in renal venous renin activity until ureteral occlusion was released and flow restored. Following release of the ureters, a prompt rise in renal venous renin was again observed within 5 min of release. Control studies of ureteral occlusion yielded a fall in renal venous renin activity following release of the ureter without administration of ethacrynic acid. These studies identify a prompt stimulatory effect of ethacrynic acid on renin release that is unrelated to volume depletion but dependent upon the presence of tubular urine flow. Although further definition of the site and characteristics of the distal tubular mechanism for stimulation of renin release requires more direct study, the data presented here indicate that changes in sodium concentration in distal tubular fluid serve as a stimulus for renin release.

Vasodilator properties of ethacrynic acid in the perfused dog kidney.

1. Ethacrynic acid reduces renal vascular resistance of the isolated dog kidney. 2. Ethacrynic acid induced natriuresis can occur despite stabilization of renal blood flow, but augmentation of blood flow increases the natriuretic response. 3. Vasodilatation and natriuresis after ethacrynic acid administration occurred together in time and were not separable. The onset and peak natriuretic and vasodilator responses frequently coincided in time. 4. Ethacrynic acid induced vasodilatation could be inhibited by loss of body fluid. The rise in resistance could be avoided by adequate volume replacement and by prevention of volume depletion.

Intravenously Given Ethacrynic Acid and Gastrointestinal Bleeding

To the Editor:— Slone et al prior to publication of their event analysis of data derived from their surveillance program, 1 graciously reported to these laboratories their suspicion that the intravenous administration of ethacrynic acid is associated with an increased incidence of gastrointestinal bleeding. The opportunity was provided to visit the two hospitals from which these cases were reported. It is our judgment, after reviewing the patients' records, that a number of factors important to consideration of this possible association are controversial, or have been ignored. Slone and colleagues noted an association between ethacrynic acid and gastrointestinal bleeding in 32 patients. Twenty-eight patients' charts were available for review. One was checked out to another department, and three were not provided because the patient was not known by name or hospital number at the record room. This may reflect key punching or other data recording errors. Progress notes, physicians' orders, and

Intravenously Given Ethacrynic Acid and Gastrointestinal Bleeding

An association (<i>P</i>&lt; 0.0001) between the administration of ethacrynic acid and the occurrence of gastrointestinal bleeding was observed during routine computer monitoring of data obtained in a drug-surveillance program. This prompted a detailed analysis wherein diagnosis, age, sex, blood urea nitrogen levels, the presence or absence of heparin sodium therapy, and the severity of illness were controlled. Even after these adjustments, the frequency of gastrointestinal bleeding among patients receiving ethacrynic acid was higher than in those patients who received furosemide, meralluride sodium and/or hydrochlorothiazide and/or chlorothiazide orally, or in those who received none of these diuretics (<i>P</i>&lt; 0.02). The difference noted with ethacrynic acid was confined to the subgroup of patients who received the drug intravenously.

Adrenergic receptor mediation of renin secretion.

ABSTRACT The role of adrenergic receptors in mediating renin secretion was studied in normal subjects with the use of upright posture and administration of diazoxide, ethacrynic acid and theophylline to provoke renin release. Each of these stimuli produced the expected rise in plasma renin activity (PRA), despite marked differences in their effect on urinary sodium excretion. In each case the increase in PRA was markedly suppressed on retesting with an infusion of either phentolamine, an alpha-adrenergic blocking agent, or propranolol, a beta-adrenergic blocking agent, whereas adrenergic blockade had little or no affect on sodium excretion. Since the stimuli chosen for provoking renin release have diverse mechanisms of action, it is noteworthy that PRA was suppressed by adrenergic blockade, regardless of the stimulus used. These findings suggest that many, if not all, of the stimuli for renin release are mediated by a common pathway which may involve alpha-and beta-adrenergic receptors. Moreover, renin re...

Ototoxicity of ethacrynic acid. Demonstrated in a human temporal bone.

ETHACRYNIC acid is a potent new diuretic which causes sodium and potassium excretion. It is especially useful in patients with refractory edema, cardiac decompensation, hepatic cirrhosis, and renal disease. Side effects such as gastrointestinal symptoms, hypoglycemia, and hyperuricemia, are not unusual. A granulocytosis and neutropenia have been reported. Recently Maher and Schreiner, 1 and Schneider and Becker 2 have reported transient hearing loss following the administration of ethacrynic acid in humans. A cysteine derivative of ethacrynic acid was withdrawn from clinical use because of high incidence of transient hearing loss. The purpose of this paper is to report a case of hearing loss and describe the pathology following the administration of ethacrynic acid. Report of a Case The patient was a 53-year-old woman who was hospitalized with hepatic cirrhosis, acute renal failure, and esophageal varices. Examination revealed a severely jaundiced individual with ascites, enlarged liver and spleen. Shortly after admission

Effect of various diuretics upon experimental cardiac necrosis

The production of a fatal “electrolyte-steroid-cardiopathy characterized by necrosis” (ESCN) is facilitated by subcutaneous or oral administration of hydrochlorothiazide or ethacrynic acid. Conversely, amiloride prevents the development of an ESCN not only when it is produced in the conventional manner, but even when its severity and lethality are increased by additional administration of either hydrochlorothiazide or ethacrynic acid.

Use of Ethacrynic Acid in Mannitol-Resistant Oliguric Renal Failure

Two patients had oliguric acute renal failure in which there was no response to intravenously administered mannitol. In both cases, diuresis resulted after simultaneous administration of mannitol and ethacrynic acid intravenously. Dialysis treatment was unnecessary. The production of a greater volume of urine decreases the tendency toward excess total body water and sodium, and extracellular potassium, and simplifies management. A therapeutic trial with both these drugs may be indicated in the oliguric phase of acute renal failure.

Use of ethacrynic acid in mannitol-resistant oliguric renal failure

Two patients had oliguric acute renal failure in which there was no response to intravenously administered mannitol. In both cases, diuresis resulted after simultaneous administration of mannitol and ethacrynic acid intravenously. Dialysis treatment was unnecessary. The production of a greater volume of urine decreases the tendency toward excess total body water and sodium, and extracellular potassium, and simplifies management. A therapeutic trial with both these drugs may be indicated in the oliguric phase of acute renal failure.

THE USE OF ETHACRYNIC ACID IN INFANTS AND CHILDREN WITH CONGESTIVE HEART FAILURE

Administration of intravenous ethacrynic acid in doses of 1 mg/kg to 8 study patients and 14 "nonstudy" patients–all of whom had congestive heart failure–is reported. No significant changes in serum electrolytes are noted following administration of the drug. In nearly all cases, diureses and clinical improvement within a few hours after administration were noted. The authors suggest that intravenous ethacrynic acid replace mercurials in the treatment of acute congestive heart failure in infants and children.

Hemodynamic effects of diuresis by ethacrynic acid in normal subjects and in patients with congestive heart failure.

Hemodynamic effects of intravenous administration of ethacrynic acid, 1 or 2 mg/kg, were studied in five normal subjects and in five patients with advanced congestive heart failure. In normal subjects, the diuresis averaged 1.2 liters in 90 minutes, resulting in a reduction in plasma volume of 14%. Stroke index fell by a mean of 21%, arteriovenous oxygen difference widened by 13%, and orthostatic tolerance was decreased. Patients in congestive heart failure showed a mean diuresis of 1.8 liters and a decrease in plasma volume of 9%. Central venous pressure fell from a mean of 16 to 10 mm Hg. Cardiac index increased by 18% from a mean of 1.8 liters/min/sq m, and stroke index rose by 11%. The arteriovenous oxygen difference narrowed from 8 to 7.1 vol%. Orthostatic stress was tolerated well.

Acute effects of oral ethacrynic acid upon total blood volume

The acute effects of oral ethacrynic acid administration upon red cell mass and plasma volume are reported in 30 patients. A significant decrease in plasma volume has been observed and is in all probability secondary to the profound diuretic effect of the drug, unlike the transient effect of phlebotomy which is largely gone by one hour. The effect of ethacrynic acid in lowering the plasma volume persists for at least 2 to 3 hours. The therapeutic implications for the patient with pulmonary edema are readily evident.

Factors influencing the electrical potential across the mucosa of rat colon.

1. An investigation has been carried out into various factors which influence the transmucosal potential difference (p.d.) of rat colon in vivo when the p.d. is either high (> 30 mV) or low (< 20 mV).2. The p.d. was uninfluenced by short duration anaesthesia with ether or pentobarbitone. When anaesthesia was prolonged for several hours, p.d. rose steadily. The gradient of p.d. along the descending colon which developed and its elimination by adrenalectomy suggested that the rise was due to increased secretion of adrenal steroids.3. P.d. was increased by Na depletion after a delay of about 18 hr and fell again following Na repletion with a similar time delay. A characteristic gradient of p.d. along the descending colon was seen.4. Both haemorrhage and anoxia caused a rapid fall of p.d. P.d. was restored rapidly to its previous level when anoxia was corrected.5. Vasopressin (I.V.) in low dose was without effect; in high dose it caused a transient fall of p.d. associated with intense vasoconstriction of gut blood vessels.6. The following factors studied were without effect on p.d.: presence of glucose within the lumen; considerable osmotic gradients across the mucosa; variation of luminal pH over the range 5.2-9.8; intravenous administration of acetazolamide, chlorothiazide, frusemide, triamterene, ethacrynic acid or ouabain. Ouabain in the luminal solution also had no effect in all but two rats in which a small fall of p.d. was seen.7. 2,4-dinitrophenol, 10(-2)M, in the lumen caused a small fall of p.d. only if the p.d. was high.8. Experiments were done to determine the effect on p.d. of altering the ionic composition of the luminal solution. When the p.d. was low (< 20 mV) alteration of [Na], [K] or [Cl] produced small absolute changes of the p.d., all of comparable magnitude. The changes could be interpreted as due to diffusion potentials resulting from the ionic gradients across the mucosa. When the p.d. was high (> 30 mV), it showed a striking dependence on the luminal [Na] only, consistent with the presence of a large p.d. due to active Na transport.