Is there any evidence to suggest IV ethacrynic acid is more effective than PO ethacrynic acid?

Is there any evidence to suggest IV ethacrynic acid is more effective than PO ethacrynic acid?

Comment by InpharmD Researcher

Comparative efficacy data on intravenous (IV) vs oral (PO) ethacrynic acid are highly limited, and much of the published literature is derived from dated studies. The most relevant study identified is a randomized, cross-over pharmacokinetic study in 10 adults with solid tumors receiving both IV and PO ethacrynic acid, which found that PO ethacrynic acid has low and variable systemic absorption rates, potentially indicating benefits with IV therapy for certain clinical scenarios; however, clinical implications beyond the pharmacokinetic assessments were not conducted in this study (Table 1).

Background

A 1971 narrative review synthesized published experimental and clinical evidence describing the pharmacologic properties, hemodynamic effects, and clinical applications of ethacrynic acid and furosemide. The review highlighted that intravenous (IV) administration of ethacrynic acid produced a rapid increase in urinary flow and natriuresis within minutes, with effects lasting several hours, and that these diuretic actions were more pronounced and prolonged in edematous patients compared to non-edematous subjects. Both drugs are rapidly absorbed after oral (PO) administration, with diuresis beginning in 20 to 60 minutes and reaching its peak in 2 hours; the diuretic effect duration is usually 6 to 8 hours. Both agents act within 5 minutes after IV administration, with peak diuresis in 30 minutes and full effect lasting 2 to 4 hours. Electrolyte excretion patterns revealed a greater chloride than sodium loss, significant kaliuresis resulting in high sodium/potassium ratios in the urine, and increased excretion of calcium and magnesium, with phosphate excretion minimally affected by ethacrynic acid but increased by furosemide. Both drugs demonstrated steep dose-response curves allowing titration from mild to severe congestive heart failure or fluid retention, maintained in the presence of hypoalbuminemia, acid-base imbalances, and low glomerular filtration rates. Despite the potent diuretic action of both drugs, side effects are relatively infrequent and close monitoring of diuretic response and electrolyte status is recommended. The review, however, did not identify any electrolyte or hemodynamic imbalances that occur more frequently or at variable rates between IV and PO ethacrynic acid. [1]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is there any evidence to suggest IV ethacrynic acid is more effective than PO ethacrynic acid?

Level of evidence

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Please see Tables 1-2 for your response.

Pharmacokinetics and Bioavailability Study of Ethacrynic Acid as a Modulator of Drug Resistance in Patients with Cancer
Design	Single-center, two-way randomized cross-over study N= 10
Objective	To investigate the pharmacokinetics and bioavailability of ethacrynic acid (EA) and describe any toxicities associated with intravenous (IV) administration
Study Groups	All patients (N= 10)
Inclusion Criteria	Histological proof of a malignant solid tumor; failed conventional therapy or had disease for which no established therapy exists; age >18 years; minimum life expectancy of 12 weeks; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; adequate bone marrow, liver, and kidney function
Exclusion Criteria	Previous therapy with thiotepa, self-medication with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) during the study
Methods	Patients were admitted 24–48 hours surrounding treatment and received standardized hydration beginning 4 hours before the first ethacrynic acid (EA) dose. Thio-TEPA 55 mg/m² was administered as a 10-minute intravenous infusion. EA 100 mg was administered by intravenous infusion over 15–17 minutes or orally in a randomized two-way crossover design to assess bioavailability, with a 12-hour washout period between routes. After the crossover portion, patients received EA and thio-TEPA according to the schedule established in the investigators' previous phase I study. Blood samples for pharmacokinetic analysis were collected before dosing and through 6 hours after EA administration, and EA plasma concentrations were measured by high-performance liquid chromatography (HPLC).
Duration	Not specified
Outcome Measures	Pharmacokinetics and bioavailability of EA; toxicities associated with intravenous administration
Baseline Characteristics		All patients (N= 10)
	Median age (range)	57 (45-74)
	Males/females	5/5
	ECOG performance status 1 2	9 (90%) 1 (10%)
Results		One-compartment (n= 2)	Two-compartment (n= 7)
	Mean AUC, mcg x hr/mL	1.26 (range 0.95-1.57)	3.41 ± 1.69*
	Mean total body clearance, mL/min	1405 (range 1060-1749)	611 ± 345
	Mean half-life, min	8 (range 7.9-8.0)	5.2 (range 3.4-9.3)
	Abbreviations: AUC, area under the curve. *Acid: 100-mg dose infused over 15 to 17 min Following IV administration, plasma ethacrynic acid concentrations were best described by a two-compartment model in 7 patients and a one-compartment model in 2 patients. Estimated oral bioavailability was 9.8% based on AUC₀–t and 20.7% based on AUC₀–∞. After PO administration, peak EA plasma concentrations were <10% of IV EA and the absolute bioavailability was less than 21% (range 7% to 35%).
Adverse Events	Burning at the injection site was the only toxicity unique to the IV route. Other toxicities included neutropenia, thrombocytopenia, nausea, vomiting, hypocalcemia, and hypomagnesemia.
Study Author Conclusions	The systemic availability of EA after PO administration is low and variable, supporting the potential utility of the IV route for the treatment of drug resistance.
Critique	The study provides valuable insights into the pharmacokinetics and bioavailability of EA, but the small sample size and variability in bioavailability limit the generalizability of the findings. The study's design does not address potential time-dependent changes in pharmacokinetics with continuous administration.

Table 1 References:
[2] Lacreta FP, Brennan JM, Nash SL, et al. Pharmakokinetics and bioavailability study of ethacrynic acid as a modulator of drug resistance in patients with cancer. J Pharmacol Exp Ther. 1994;270(3):1186-1191.

Cardiorenal hemodynamic effects of ethacrynic acid
Design	Prospective, single-center study with acute and subacute components N= N/A (multiple overlapping cohorts)
Objective	To compare the effects of ethacrynic acid on systemic hemodynamics, renal function, and electrolyte excretion in patients with various clinical disorders and in normal persons
Study Groups	Hypertensive patients receiving IV ethacrynic acid (n= 6) Normotensive subjects receiving IV ethacrynic acid (n= 3) Hypertensive patients receiving IV saline (n= 5) Patients with edema receiving IV ethacrynic acid (n= 5)
Inclusion Criteria	Patients from the wards of the University Hospitals, Iowa City, including hypertensive and normotensive subjects, and patients with edema
Exclusion Criteria	Not specified
Methods	Hospitalized hypertensive patients, normotensive subjects, patients with edema, and one patient with diabetes insipidus were evaluated. Acute studies assessed the effects of intravenous ethacrynic acid (45–90 mg) on renal function and cardiac hemodynamics; hypertensive control patients received an equivalent volume of intravenous isotonic saline. Renal function was measured before and at 30, 60, and 90 minutes after treatment, and cardiac hemodynamic measurements were obtained at the same time points. A subgroup of hypertensive and normotensive subjects also received oral ethacrynic acid 1.5 mg/kg/day for 4–7 days, with renal function, cardiac hemodynamics, body weight, blood volume, laboratory parameters, and urinalysis assessed before and after treatment. An additional patient with diabetes insipidus underwent evaluation after intravenous chlorothiazide and intravenous ethacrynic acid, followed by graded oral ethacrynic acid (100–300 mg/day).
Duration	Acute study: Baseline and 30-, 60-, and 90-minute assessments following IV administration Subacute study: 4–7 days of oral ethacrynic acid
Outcome Measures	Canges in systemic hemodynamics and renal function; electrolyte excretion, urine volume, and pH changes
Baseline Characteristics		Hypertensive patients receiving ethacrynic acid (n= 6)	Normotensive subjects receiving ethacrynic acid (n= 3)	Hypertensive patients receiving saline (n= 5)
	Age, years (range)	41.3 (30-51)	34 (23-43)	45 (23-62)
	Male	4	1	Not specified
	Baseline characteristics did not differ significantly between hypertensive patients receiving IV ethacrynic acid and saline controls.
Results	Acute IV ethacrynic acid produced rapid diuresis, with increased urine volume and urinary sodium, potassium, and chloride excretion in hypertensive, normotensive, and edema patients. Glomerular filtration rate decreased in hypertensive, normotensive, and edema patients, whereas renal plasma flow did not change significantly. In hypertensive patients, cardiac index decreased from 3.1 to 2.5 L/min/m² at 30 minutes (p< 0.05), right atrial pressure decreased from 3.1 to 2.1 mm Hg (p< 0.05), and total systemic resistance increased from 2,380 to 2,865 dyn·sec·cm⁻⁵ (p< 0.01). Mean arterial pressure was significantly lower than baseline at 90 minutes. After 4–7 days of oral ethacrynic acid, hypertensive patients had reduced body weight (161 ± 17.9 to 156 ± 17.8 lb; p< 0.05), serum potassium (4.1 ± 0.2 to 3.6 ± 0.1 mEq/L; p< 0.05), and serum chloride (101 ± 2.2 to 96 ± 1.4 mEq/L; p< 0.001), with increased serum carbon dioxide (25 ± 1.6 to 27 ± 1.4 mEq/L; p< 0.05) and uric acid (4.7 ± 0.3 to 6.9 ± 0.4 mg/100 mL; p< 0.001). Renal and cardiac hemodynamic parameters were not significantly different from pretreatment values after oral therapy.
Adverse Events	Mild nausea reported after oral and intravenous doses. No adverse effects on hemopoietic, hepatic, or central-nervous-system functions were noted.
Study Author Conclusions	Ethacrynic acid is a potent diuretic that causes a rapid onset of diuresis with significant electrolyte excretion. It is effective in increasing urine osmolality in patients with diabetes insipidus and has minimal systemic hemodynamic effects.
Critique	The study provides valuable insights into the effects of ethacrynic acid on renal and systemic hemodynamics. However, the small sample size and lack of a control group for some comparisons may limit the generalizability of the findings. The study's design does not account for long-term effects or potential interactions with other medications.

Table 2 References:
[3] Nash HL, Fitz AE, Wilson WR, Kirkendall WM, Kioschos JM. Cardiorenal hemodynamic effects of ethacrynic acid. Am Heart J. 1966;71(2):153-165. doi:10.1016/0002-8703(66)90178-5