Ethacrynic Acid

Mechanism of Action

The main site of action is limited to the ascending limb of the nephron’s loop of Henle, which is responsible for sodium and chloride reabsorption. Normally, the ascending loop of Henle reabsorbs 25% to 30% of the tubular fluid’s sodium while remaining relatively impermeable to water (except in the presence of antidiuretic hormone, which allows water reabsorption through aquaporin channels). By inhibiting active sodium transport via inhibition of the Na-K-2Cl symporter, ethacrynic acid prevents the kidney from forming hypotonic urine. These ions retained in tubular fluid create an electrochemical gradient that prevents reabsorption of calcium and magnesium as well. In turn, this increases the osmotic force inside the renal tubule and prevents water from leaking into the renal interstitium. As a result, ethacrynic acid leads to increased natriuresis and diuresis.[5][6][7][2] Ethacrynic acid has also been demonstrated to cause venous dilation contributing to rapid pulmonary decongestion even before its onset of diuresis.[7]

Administration

Intravenous application is the preferred agent in inpatient settings for the management of flash pulmonary edema and treatment-resistant forms of edema. Ethacrynic acid may be administered via IV at 0.5 to 1 mg/kg. Oral forms are also available at doses of 20 mg to 400 mg given one to four times daily, though typical doses are 50 to 200 mg daily. The onset of action of the oral form occurs with peak diuresis at about 2 to 4 hours, showing complete diuresis within 6 to 8 hours. However, the onset of action intravenously is approximately 5 minutes, with a peak of activity occurring at 30 minutes.[8][7]

Adverse Effects

Since diuresis and natriuresis occur so rapidly using ethacrynic acid, reductions in blood volume lead to a decrease in mean arterial pressure. Reduced cardiac index and reflex tachycardia can also occur due to the sudden decrease in preload. [3] Within one use, intravenous ethacrynic acid can precipitate immediate volume depletion that can potentially be life-threatening.[8] Because of this, close monitoring of blood pressure is advisable during use. 

When diuresis is excessive, decreased renal blood flow and glomerular filtration rate result in severe azotemia and uremia.[9] Orthostatic hypotension or even shock can ensue if large amounts of water and sodium are lost too quickly. With repeated uses of intravenous ethacrynic acid, hypokalemic metabolic acidosis and magnesium depletion can occur as a direct result of its action on the loop of Henle.[8] Potassium losses can precipitate digoxin toxicity in heart failure patients as well as muscular weakness and intestinal atony.  

Of note, the most novel adverse effect of ethacrynic acid is ototoxicity, which can be seen after only one use, especially when delivered intravenously.[8][9] The stria vascularis is a secretory tissue of the lateral wall of the cochlear duct. Its function is to secrete endolymph while simultaneously maintaining its gradient of potassium ions to sodium ions, contributing to the resting endocochlear potential (EP). The positive EP usually rests at +90mV and is significantly reduced after a single injection of ethacrynic acid in animal models. This data suggests that the stria vascularis is a major target for ethacrynic acid. Further analysis discovered that the reduction in EP is due to decreased blood flow to the stria vascularis caused by ethacrynic acid’s activation of renin secreting cells in the cochlea. Similar to human cases, the damage replicated in animal models was only transient, recovering within hours of injection.[5]

Transient hearing loss can be observed in patients after one-time use of intravenous ethacrynic acid and can occur as quickly as 15 minutes after administration. Transient hearing loss has also been observed after long-term oral use, particularly in patients with decreased renal function since the kidneys metabolize ethacrynic acid.[9] When using ethacrynic acid in patients already treated with ototoxic drugs such as aminoglycosides or cisplatin, the side effects are synergistic; this can lead to permanent cochlear hair cell loss due to cochlear ischemia. Transient tinnitus, vertigo, and permanent hearing loss, including bilateral deafness, are significant consequences of ethacrynic acid, contraindicating its use in patients receiving treatment with other ototoxic drugs.[9]

Gastrointestinal side effects are less common and include nausea, vomiting, diarrhea, and epigastric pain that are usually temporary. In a few rare cases, ethacrynic acid has been implicated in pancreatitis and hepatitis, though causality remains unclear. Further, similar to thiazides, because it is an organic acid and can compete with urea in the nephron, ethacrynic acid can cause an increase in serum uric acid, precipitating acute gout.[9] Lastly, ethacrynic acid can cause hemolysis via inhibition of red cell ATPase and glycolytic enzymes in vitro, which becomes clinically relevant during the administration of blood products in the elderly. It is common practice to administer loop diuretics to elderly patients during blood product transfusion to avoid exacerbating symptoms of congestive heart failure. Hemolysis occurring with transfusion leads to an increase in the plasma concentration of ethacrynic acid, which could potentiate the adverse effects discussed above.[10]

Contraindications

Ethacrynic acid is contraindicated in patients already receiving treatment with other ototoxic drugs such as cisplatin or gentamycin. When taken alone, ototoxic drugs like gentamycin have a relatively low uptake into the cochlea, explaining why they rarely cause hearing loss. However, when taken with high doses of ethacrynic acid, permanent hearing loss can be observed. This effect appears to be caused by ethacrynic acid's effect on cochlear tight junctions. Damage to these tight junctions leads to increased permeability and a weakened blood-cochlear barrier allowing entry of ototoxic drugs.[5] 

Monitoring

Ethacrynic acid is a rapid-acting loop diuretic. Onset can occur at 5 minutes with a peak onset of action within 30 minutes. Because it has 100% bioavailability, ethacrynic acid dosing is according to the weight of the patient. Intravenous doses usually range between 0.5 to 1mg/kg and typically do not exceed 100 mg in a single dose.[8] Monitoring is similar to that of other loop diuretics. Since electrolyte abnormalities and volume depletion are of concern, kidney function, creatinine levels, basic electrolytes, and blood pressure are monitored early in the course of use.[3]

Toxicity

Currently, there is no antidote described in the literature for the toxicity of ethacrynic acid. Toxicity usually occurs in elderly patients with diminished renal function leading to volume depletion and, in some cases, toxicity. When adverse side effects occur, rapid discontinuation of ethacrynic acid and supportive care can lead to the resolution of symptoms.[3]

Enhancing Healthcare Team Outcomes

Ethacrynic acid is usually reserved for patients with sulfa allergies. The interprofessional healthcare team should be aware of the drug's rapid onset and monitor the dosages of the drug to avoid hypovolemia and electrolyte imbalances. Pharmacists and clinicians are to pay close attention to patients with renal failure and adjust therapeutic levels of ethacrynic acid accordingly. Nurses should be aware of the signs of adverse events so they can report these promptly to the ordering clinician. To improve outcomes, monitor blood pressure, and avoid concurrent use of other ototoxic medications. If ototoxicity, hepatotoxicity, or electrolyte imbalances are suspected, ethacrynic acid therapy should stop immediately, and the patient should receive appropriate supportive care and symptom management. Utilizing interprofessional team strategies will result in better therapeutic outcomes and fewer adverse events with ethacrynic acid, driving better patient outcomes. [Level 5]