Furosemide

Pharmaceuticals -> Diuretics

Pharmaceuticals -> Used in Switzerland

Pharmaceutical

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

log Kow = 2.03

2.03

2.03

Crystals from aqueous ethanol

White to off-white crystalline powder

Fine, white to slightly yellow, crystalline powder

less than 1 mg/mL at 73 °F (NTP, 1992)

The sodium salt can be recrystallized from water; the solubility of the salt in water at room temperature is 6%. /Furosemide sodium salt/

In water, 73.1 mg/L at 30 °C

Slightly soluble in water

Slightly soluble in chloroform, ether. Soluble in acetone, methanol, DMF, aqueous solutions above pH 8.0. Less soluble in ethanol.

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Loop Diuretics

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Pharmaceuticals

Diuretics

Active Ingredients (Furosemide) -> FDA Greenbook

Pharmaceuticals -> UK Veterinary Medicines Directorate List

403 °F (decomposes) (NTP, 1992)

206 °C

295 °C

Furosemide is an odorless white to slightly yellow crystalline powder. A diuretic drug. Almost tasteless. (NTP, 1992)

Solid

Stable under recommended storage conditions.

Commercially available 40-mg furosemide tablets have an expiration date of 5 years and the commercially available injection has an expiration date 42 months following the date of manufacture. The 20-mg tablets do not have a specific expiration dating period.

This chemical does not meet GHS hazard criteria for 0.4% (1 of 240) of reports.

Danger

H315 (11.7%): Causes skin irritation [Warning Skin corrosion/irritation]

P203, P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 240 reports by companies from 25 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

SYMPTOMS: Gastrointestinal system reactions to this compound may include anorexia, oral and gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice and pancreatitis. Central nervous system reactions may include dizziness, vertigo, paresthesia, headache, xanthopsia, blurred vision, tinnitus and hearing loss. Hematologic reactions may include anemia, leukopenia, agranulocytosis, thrombocytopenia and aplastic anemia. Dermatologic-hypersensitivity reactions may include purpura, photosensitivity, rash, urticaria, necrotizing angiitis, exfoliative dermatitis, erythema multiforme and pruritus. Cardiovascular reactions may include orthostatic hypotension. Other symptoms may include hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness, urinary bladder spasm and thrombophlebitis. Fluid and electrolyte imbalance, allergies and liver damage may also occur. It may also cause tetany and dehydration. Other symptoms may include increased thirst, lethargy, drowsiness, fatigue, oliguria, tachycardia, reduction of plasma volume, circulatory collapse, thrombosis, embolism, convulsions, ataxia, paralysis and collapse.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including furosemide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Furosemide is included on this list.

Oral dosage form new animal drugs. Furosemide. ... (1) Cattle ... Indications for use. For treatment of physiological parturient edema of the mammary gland and associated structures. Limitations. Treatment not to exceed 48 hours post-parturition. Milk taken during treatment and for 48 hours after the last treatment must not be used for food. Cattle must not be slaughtered for food within 48 hours following last treatment. (2) Dogs ... Indications for use-(A) For treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema. (B) For treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency. (3) Cats ... Indications for use. For treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema.

Implantation or injectable dosage form new animal drugs. Furosemide. ... (1) Dogs and cats ...Indications for use. For the treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema. ... (2) Horses ... Indications for use. For the treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency, and acute noninflammatory tissue edema. Limitations. Do not use in horses intended for human consumption. ... (3) Cattle ... Indications for use. For the treatment of physiological parturient edema of the mammary gland and associated structures. Limitations. Treatment not to exceed 48 hours post-parturition. Milk taken during treatment and for 48 hours (four milkings) after the last treatment must not be used for food. Cattle must not be slaughtered for food within 48 hours following last treatment.

BENET LZ; PHARMACOKINETICS/PHARMACODYNAMICS OF FUROSEMIDE IN MAN: REVIEW; J PHARMACOKINET BIOPHARM 7 (FEB): 1-27 (1979); PHARMACOKINETICS IN NORMAL & DISEASED SUBJECTS, METABOLISM, & RELATIONSHIPS BETWEEN DOSAGE & PHARMACOKINETIC RESPONSE ARE REVIEWED.

DHHS/NTP; Toxicology & Carcinogenesis Studies of Furosemide in F344/N Rats and B6C3F1 Mice Technical Report Series No. 356 (1989) NIH Publication No. 89-2811

Aranda JV et al; Furosemide and vitamin E. Two problem drugs in neonatology.; Pediatr Clin North Am 33 (3): 583-602 (1986). This article focuses on some of the problems encountered with two of the drugs currently given to newborns.

Hammarlund-Udenaes M, Benet LZ; Furosemide pharmacokinetics and pharmacodynamics in health and disease--update; J Pharmacokinet Biopharm 17 (Feb) 1-46 (1989). A review of the pharmacokinetics and pharmacodynamics of furosemide is presented, including iv and oral data for healthy volunteers and for patients with various disease states. Inter and intraindividual variations in bioavailability, the metabolism of furosemide to its glucuronide conjugate, and the pharmacokinetics of furosemide in children are discussed.

Ponto LL, Schoenwald RD; Furosemide (frusemide). A pharmacokinetic/pharmacodynamic review (Part II).; Clin Pharmacokinet 18 (6): 460-71 (1990). The pharmacodynamics of the drug furosemide are examined, and various areas for future study are suggested.

FUROSEMIDE may undergo hydrolysis at sufficiently low pH. The pH of aqueous solutions should be maintained in the basic range to prevent hydrolysis. Alcohol has been shown to improve the stability of this compound. Incompatible with strong oxidizing agents (NTP, 1992).

Incompatible materials: Strong oxidizing agents.

Furosemide is soluble in alkaline soln that is prepared as a mildly buffered alkaline product. It should not be mixed with acidic solns have a pH below 5.5. Furosemide may precipitate if combined with ascorbic acid, epinephrine, norepinephrine, or tetracycline. The acidic pH of aminoglycoside admixtures may cause transient cloudiness or frank precipitation if furosemide is added, depending on which aminoglycoside is used & the concn of the additives. Avoiding the admixture of furosemide & aminoglycosides has been recommended.

Furosemide may precipitate if mixed with milrinone lactate infusions.

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

Keep container tightly closed in a dry and well-ventilated place.

Furosemide injection should be stored at a temperature of 15-30 °C and protected from light; injections having a yellow color should not be used. Exposure of furosemide tablets to light may cause discoloration; discolored tablets should not be dispensed. Furosemide tablets should be stored and dispensed in well-closed, light-resistant containers at a controlled room temperature of 15-30 °C. ... The 20-mg tablets do not have a specific expiration dating period. Furosemide oral solutions should be stored at 15-30 °C and protected from light and freezing; once opened, unused portions of the oral solution should be discarded after the time period recommended by the manufacturer.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with 60-70% ethanol and transfer the dampened material to a suitable container. Use absorbent paper dampened with 60-70% ethanol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with 60-70% ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.

Precautions for safe handling: Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Impervious clothing. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Methotrexate and other drugs that, like Lasix, undergo significant renal tubular secretion may reduce the effect of Lasix. Conversely, Lasix may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both Lasix and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of Lasix.

Phenytoin interferes directly with renal action of Lasix. There is evidence that treatment with phenytoin leads to decreased intestinal absorption of Lasix, and consequently to lower peak serum furosemide concentrations.

Lasix may decrease arterial responsiveness to norepinephrine. However, norepinephrine may still be used effectively.

There is a risk of ototoxic effects if cisplatin and Lasix are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if Lasix is not given in lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment.

For more Interactions (Complete) data for Furosemide (36 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 110(SRC), determined from a structure estimation method(2), indicates that furosemide is expected to have high mobility in soil(SRC). The pKa of furosemide is 3.9(3), indicating that this compound will exist almost entirely in anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of the anion from moist soil is not expected because anions do not volatilize(SRC). Furosemide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.1X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Furosemide may biodegrade in soil based upon half-lives of 14-20 days in river sediments(5).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 110(SRC), determined from a structure estimation method(2), indicates that furosemide is expected to adsorb to suspended solids and sediment(SRC). A pKa of 3.9(3) indicates furosemide will exist almost entirely in the anion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected(SRC). Furosemide is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow of 2.03(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low. Furosemide had a biodegradation half-life of 14-20 days in various river sediments under aerobic conditions; furosemide was degraded at a slower rate under anaerobic conditions(7).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), furosemide, which has an estimated vapor pressure of 3.1X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase furosemide may be removed from the air by wet and dry deposition(SRC). Furosemide absorbs UV light at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Furosemide is white or slightly yellow, solid powder or crystals. Furosemide is used to treat edema associated with many diseases (either as the sole drug or as an adjunct to other antihypertensives). HUMAN STUDIES: Overdoses of diuretics are uncommon and infrequently serious. Problems most frequently involve chronic over medication or poor monitoring and/or lack of anticipation of drug interactions or not compensating for concomitant hepatic or renal dysfunction. Main toxic effects are on the kidneys with diuresis of water, sodium, and potassium leading most frequently to a hyponatremic, hypokalemic, and hypochloremic dehydration. More caution is warranted with patients at higher risk for abnormal renal function including patients with any renal disease, diabetes mellitis, and borderline fluid and/or electrolyte status. In a hospital-based study of adverse reactions to medications there was a 21% rate of adverse affects to frusemide with most common ones being hypovolemia, hyperuricemia, and hypokalemia which for the most part were mild, but the rate and severity increased with increasing daily doses. Hypersensitivity reactions such as rash, photosensitivity, thrombocytopenia, and pancreatitis are rare. Life threatening hyperkalemia and reversible renal failure occurred in an elderly male taking captopril concomitantly with furosemide. Acute rhabdomyolysis and myoglobinuria due to hypokalaemia occurred in a 74-year-old male taking furosemide. Severe anaphylactic reaction to furosemide involving urticaria; angioedema and hypotension occurred in an adult 5 minutes after receiving intravenous furosemide. Furosemide abuse (400 mg daily) was associated with severe hyponatremia and central pontine myelinolysis. Self-administration of furosemide over 6 years resulted in calcification of the renal medulla. Nephrocalcinosis and nephrolithiasis occurred in 5 children after treatment with furosemide. It has also reported nephrocalcinosis in premature infants being treated with furosemide. Cholelithiasis in infants was caused by furosemide. Tachycardia was reported following a high dose intravenous regimen using furosemide. Renal calcifications were encountered in premature infants when given furosemide. Furosemide-induced renal calcifications in low birth weight infants may lead to glomerular and tubular dysfunction in the long-term. A concentration-dependent increase in the frequency of chromosomal aberrations was observed in human lymphocytes exposed in vitro to furosemide for 24 and 72 hr. No such effect was detected in the human fibroblast cell line. ANIMAL STUDIES: Chronic administration to rats has caused tubular degeneration in the kidneys. Calcification and damage to the renal parenchyma occurred in a subchronic study in dogs. Developmental studies have been conducted in mice, rats and rabbits. An increase in the incidence and severity of hydronephrosis (distention of the renal pelvis and occasionally the ureters) was seen in a mouse study and one of three rabbit studies. In male mice treated intraperitoneally with furosemide at 0.3-50 mg/kg bw, a non-dose-dependent increase in the percentage of meiotic cells with chromosomal aberrations was observed during the whole spermatogenic cycle. Furosemide was tested over a wide range of doses (0, 100, 333, 1000, 3333, and 10,000 ug/plate) in four Salmonella typhimurium strains (TA98, TA100, TA1535, and TA1537) with and without metabolic activation. Furosemide was negative in these tests and the highest ineffective dose level tested in any Salmonella tester strain was 10,000 ug/plate. Furosemide was reported to induce mutations in L5178Y mouse lymphoma cells in the presence of an exogenous metabolic system only at the highest concentration tested (1500 ug/mL). It was also reported to induce sister chromatid exchange and chromosomal aberrations in Chinese hamster CHO cells at 3750 and 500 ug/mL in the presence and absence of an exogenous metabolic system. Furosemide induced chromosomal damage in Chinese hamster lung fibroblasts in vitro, but only in the absence of an exogenous metabolic system. ECOTOXICITY STUDIES: Furosemide in combination with other drugs found in waste water was genotoxic to zebrafish, and exhibited toxic effects on riverine microbial communities.

Toxicity with furosemide manifests as extensions of its diuretic activity. The main signs and symptoms of overdose with furosemide are blood volume reduction, dehydration, electrolyte imbalance, hypotension, hypochloremic alkalosis, and hypokalemia.

/AQUATIC SPECIES/ Over the past few years, the increasing and uncontrolled use of pharmaceutical substances in agriculture, fish farming, human health and in veterinary medicine, together with an improper use of out-of-date medicines, has led to a consequent increase in the environmental problems linked to their disposal. In some Italian waste water treatment plants were found furosemide, a diuretic; ranitidine, an antiulcer drug; bezafibrate, a lipid regulator and ibuprofen, a painkiller. The present paper shows, by means of the synergic application of three tests (the Comet Test, the Diffusion Assay and the RAPD-PCR technique), how the DNA of zebrafish can be damaged after exposure to the above mentioned drugs. The data from the Comet Test, the Diffusion Assay and the RAPD-PCR technique were generally in agreement; these results show that all four drugs are genotoxic.

/AQUATIC SPECIES/ Although pharmaceutical and therapeutic products are widely found in the natural environment, there is limited understanding of their ecological effects. ...Rotating annular bioreactors /were used/ to assess the impact of 10 ug/L of the selected pharmaceuticals ibuprofen, carbamazepine, furosemide, and caffeine on riverine biofilms. After 8 weeks of development, community structure was assessed using in situ microscopic analyses, fluor-conjugated lectin binding, standard plate counts, fluorescent in situ hybridization, carbon utilization spectra, and stable carbon isotope analyses. The biofilm communities varied markedly in architecture although only caffeine treated biofilms were significantly thicker. Cyanobacteria were suppressed by all 4 compounds, whereas the nitrogen containing caffeine, furosemide, and carbamazepine increased algal biomass. Ibuprofen and carbamazepine reduced bacterial biomass, while caffeine and furosemide increased it. Exopolymer content and composition of the biofilms was also influenced. Significant positive and negative effects were observed in carbon utilization spectra. In situ hybridization analyses indicated all treatments significantly decreased the gamma-proteobacterial populations and increased beta-proteobacteria. Ibuprofen in particular increased the alpha-proteobacteria, beta-proteobacteria, cytophaga-flavobacteria, and SRB385 probe positive populations. Caffeine and carbamazepine additions resulted in significant increases in the high GC354c and low GC69a probe positive cells. Live-dead analyses of the biofilms indicated that all treatments influenced the ratio of live-to-dead cells with controls having a ratio of 2.4, carbamazepine and ibuprofen being 3.2 and 3.5, respectively, and furosemide and caffeine being 1.9 and 1.7, respectively. Stable isotope analyses of the biofilms indicated delta 13C values shifted to more negative values relative to control biofilms. This shift may be consistent with proportional loss of cyanobacteria and relative increase in algal biomass rather than incorporation of pharmaceutical carbon into microbial biofilm. Thus, at 10 ug/L levels pharmaceuticals exhibit both nutrient-like and toxic effects on riverine microbial communities.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of May 1, 2017: http://actor.epa.gov/dashboard/]

The following link will take the user to the National Toxicology Program (NTP) Test Status of Agents Search page, which tabulates the results and current status of tests such as "Short-Term Toxicity Studies", "Long-term Carcinogenicity Studies", "Developmental Studies", "Genetic Toxicology Studies", etc., performed with this chemical. Testing status for furosemide is available.[Available from, as of July 26, 2017: https://ntpsearch.niehs.nih.gov/?e=True&ContentType=Testing+Status]

Samples collected May 18-19 and Oct 19-20, 2009 from a wastewater treatment plant in Los Angeles, CA contained furosemide at mean concentrations of 93 and 57 ng/L, respectively(1). Furosemide was removed 0-17% and 15-62% in samples collected Jan-Mar and Jun-Sep 2004, respectively, from six sewage treatment plants in Italy(2). Furosemide was detected in 100, 96 and 83% of waste water influent, effluent and sludge samples at respective LOQ's of 4.0 ng/L, 2.0 ng/L and 1.0 ng/g, samples were collected from three Spanish treatment plants in eight campaigns over a two year period (July 2007-March 2009)(3). Furosemide was detected in the effluents of waste water treatment plants in Spain at 128-937 ng/L(4).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of furosemide can be estimated to be 110(SRC). According to a classification scheme(2), this estimated Koc value suggests that furosemide is expected to have high mobility in soil. The pKa of furosemide is 3.9(3), indicating that this compound will exist almost entirely in anion form in the environment and anions generally do not adsorb to soils containing organic carbon and clay than their neutral counterparts(4).

/HUMAN EXPOSURE STUDIES/ The pharmacokinetics and pharmacodynamics of the combination of amiloride (2 x 2.5 mg) and long acting furosemide (2 x 10 mg) were compared with amiloride (5 mg) and furosemide (20 mg) in 12 healthy male volunteers aged 26.2 + or - 1.6 yr and weighing 68.8 + or - 6.2 kg, after random order administration. Furosemide and amiloride plasma or urine concn were determined by HPLC with fluorimetric detection. The rate of absorption (tmax = 3 hr) and the bioavailability of the two diuretics were not significantly modified by their combination. Furosemide plasma half life was 2.77 + or - 1.04 hr after the combination treatment and 2.76 + or - 0.98 hr alone, amiloride plasma half life was respectively 15.7 + or - 4.6 hr and 14.6 + or - 3.7 hr. The urinary elimination of furosemide was significantly higher in the 2-4 hr interval in the combination treatment, accompanying its delayed maximum effect of diuresis. A synergistic effect was observed after the combination administration of the two diuretics; between the 2nd and the 8th hour, the sodium elimination was significantly increased (p< 0.01) and the potassium excretion was significantly decreased (p= 0.05). After a single dose, no modification of plasma or erythrocyte magnesium levels was observed. This study shows that the combination of the two drugs entails a synergy of their activities which does not involve pharmacokinetic changes.

/HUMAN EXPOSURE STUDIES/ Interactions between sodium and calcium regulating systems are poorly characterized but clinically important. Parathyroid hormone (PTH) levels are increased shortly after furosemide treatment by an unknown mechanism, and this effect is blunted by the previous administration of a calcimimetic in animal studies. Here, we explored further the possible underlying mechanisms of this observation in a randomized crossover placebo-controlled study performed in 18 human males. Volunteers took either cinacalcet (60 mg) or placebo and received a 20 mg furosemide injection 3 hr later. Plasma samples were collected at 15-min intervals and analyzed for intact PTH, calcium, sodium, potassium, magnesium, phosphate, plasma renin activity (PRA), and aldosterone up to 6 hr after furosemide injection. Urinary electrolyte excretion was also monitored. Subjects under placebo presented a sharp increase in PTH levels after furosemide injection. In the presence of cinacalcet, PTH levels were suppressed and marginal increase of PTH was observed. No significant changes in electrolytes and urinary excretion were identified that could explain the furosemide-induced increase in PTH levels. PRA and aldosterone were stimulated by furosemide injection but were not affected by previous cinacalcet ingestion. Expression of NKCC1, but not NKCC2, was found in parathyroid tissue. In conclusion, our results indicate that furosemide acutely stimulates PTH secretion in the absence of any detectable electrolyte changes in healthy adults. ...

/SIGNS AND SYMPTOMS/ The principal signs and symptoms of overdose with Lasix are dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and are extensions of its diuretic action.

/SIGNS AND SYMPTOMS/ Furosemide may produce profound diuresis resulting in fluid and electrolyte depletion. Fluid and electrolyte depletion are especially likely to occur when large doses are given and/or in patients with restricted sodium intake.

For more Human Toxicity Excerpts (Complete) data for Furosemide (20 total), please visit the HSDB record page.

AEROBIC: Furosemide is stated as not readily biodegraded(1). Furosemide had a biodegradation half-life of 14-20 days in various river sediments under aerobic conditions; furosemide was degraded at a slower rate under anaerobic conditions(2). In an Australian sewage treatment plant, 20% of furosemide was removed, 15% was attributed to biodegradation(3).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including furosemide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Furosemide is included on this list.

Oral dosage form new animal drugs. Furosemide. ... (1) Cattle ... Indications for use. For treatment of physiological parturient edema of the mammary gland and associated structures. Limitations. Treatment not to exceed 48 hours post-parturition. Milk taken during treatment and for 48 hours after the last treatment must not be used for food. Cattle must not be slaughtered for food within 48 hours following last treatment. (2) Dogs ... Indications for use-(A) For treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema. (B) For treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency. (3) Cats ... Indications for use. For treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema.

Implantation or injectable dosage form new animal drugs. Furosemide. ... (1) Dogs and cats ...Indications for use. For the treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema. ... (2) Horses ... Indications for use. For the treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency, and acute noninflammatory tissue edema. Limitations. Do not use in horses intended for human consumption. ... (3) Cattle ... Indications for use. For the treatment of physiological parturient edema of the mammary gland and associated structures. Limitations. Treatment not to exceed 48 hours post-parturition. Milk taken during treatment and for 48 hours (four milkings) after the last treatment must not be used for food. Cattle must not be slaughtered for food within 48 hours following last treatment.

C03CA01

C - Cardiovascular system

QC - Cardiovascular system

C03CA01

Furosemide manages hypertension and edema associated with congestive heart failure, cirrhosis, and renal disease, including the nephrotic syndrome. Furosemide is a potent loop diuretic that works to increase the excretion of Na+ and water by the kidneys by inhibiting their reabsorption from the proximal and distal tubules, as well as the loop of Henle. It works directly acts on the cells of the nephron and indirectly modifies the content of the renal filtrate. Ultimately, furosemide increases the urine output by the kidney. Protein-bound furosemide is delivered to its site of action in the kidneys and secreted via active secretion by nonspecific organic transporters expressed at the luminal site of action. Following oral administration, the onset of the diuretic effect is about 1 and 1.5 hours, and the peak effect is reached within the first 2 hours. The duration of effect following oral administration is about 4-6 hours but may last up to 8 hours. Following intravenous administration, the onset of effect is within 5 minutes, and the peak effect is reached within 30 minutes. The duration of action following intravenous administration is approximately 2 hours. Following intramuscular administration, the onset of action is somewhat delayed.

Furosemide promotes diuresis by blocking tubular reabsorption of sodium and chloride in the proximal and distal tubules, as well as in the thick ascending loop of Henle. This diuretic effect is achieved through the competitive inhibition of sodium-potassium-chloride cotransporters (NKCC2) expressed along these tubules in the nephron, preventing the transport of sodium ions from the lumenal side into the basolateral side for reabsorption. This inhibition results in increased excretion of water along with sodium, chloride, magnesium, calcium, hydrogen, and potassium ions. As with other loop diuretics, furosemide decreases the excretion of uric acid. Furosemide exerts direct vasodilatory effects, which results in its therapeutic effectiveness in the treatment of acute pulmonary edema. Vasodilation leads to reduced responsiveness to vasoconstrictors, such as angiotensin II and noradrenaline, and decreased production of endogenous natriuretic hormones with vasoconstricting properties. It also leads to increased production of prostaglandins with vasodilating properties. Furosemide may also open potassium channels in resistance arteries. The main mechanism of action of furosemide is independent of its inhibitory effect on carbonic anhydrase and aldosterone.

Though both in vivo and in vitro studies have demonstrated an anticonvulsant effect of the loop diuretic furosemide, the precise mechanism behind this effect is still debated. The current study investigates the effect of furosemide on Cs-induced epileptiform activity (Cs-FP) evoked in area CA1 of rat hippocampal slices in the presence of Cs(+) (5mM) and ionotropic glutamatergic and GABAergic receptor antagonists. As this model diverges in several respects from other epilepsy models it can offer new insight into the mechanism behind the anticonvulsive effect of furosemide. The present study shows that furosemide suppresses the Cs-FP in a dose-dependent manner with a near complete block at concentrations = 1.25 mM. Because furosemide targets several types of ion transporters we examined the effect of more selective antagonists. Bumetanide (20 uM), which selectively inhibits the Na-K-2Cl co-transporter (NKCC1), had no significant effect on the Cs-FP. VU0240551 (10 uM), a selective antagonist of the K-Cl co-transporter (KCC2), reduced the ictal-like phase by 51.73 +/- 8.5% without affecting the interictal-like phase of the Cs-FP. DIDS (50 uM), a nonselective antagonist of Cl(-)/HCO3(-)-exchangers, Na(+)-HCO3(-)-cotransporters, chloride channels and KCC2, suppressed the ictal-like phase by 60.8 +/- 8.1% without affecting the interictal-like phase. At 500 uM, DIDS completely suppressed the Cs-FP. Based on these results we propose that the anticonvulsant action of furosemide in the Cs(+)-model is exerted through blockade of the neuronal KCC2 and Na(+)-independent Cl(-)/HCO3(-)-exchanger (AE3) leading to stabilization of the activity-induced intracellular acidification in CA1 pyramidal neurons.

Sodium chloride reabsorption in the thick ascending limb of the loop of Henle is mediated by the Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). The loop diuretic furosemide is a potent inhibitor of NKCC2. However, less is known about the mechanism regulating the electrolyte transporter. Considering the well-established effects of nitric oxide on NKCC2 activity, cGMP is likely involved in this regulation. cGMP-dependent protein kinase I (cGKI; PKGI) is a cGMP target protein that phosphorylates different substrates after activation through cGMP. We investigated the potential correlation between the cGMP/cGKI pathway and NKCC2 regulation. We treated wild-type (wt) and cGKIa-rescue mice with furosemide. cGKIa-rescue mice expressed cGKIa only under the control of the smooth muscle-specific transgelin (SM22) promoter in a cGKI deficient background. Furosemide treatment increased the urine excretion of sodium and chloride in cGKIa-rescue mice compared to that in wt mice. We analyzed the phosphorylation of NKCC2 by western blotting and immunostaining using the phosphospecific antibody R5. The administration of furosemide significantly increased the phosphorylated NKCC2 signal in wt but not in cGKIa-rescue mice. NKCC2 activation led to its phosphorylation and membrane translocation. To examine whether cGKI was involved in this process, we analyzed vasodilator-stimulated phosphoprotein, which is phosphorylated by cGKI. Furosemide injection resulted in increased vasodilator-stimulated phosphoprotein phosphorylation in wt mice. We hypothesize that furosemide administration activated cGKI, leading to NKCC2 phosphorylation and membrane translocation. This cGKI-mediated pathway could be a mechanism to compensate for the inhibitory effect of furosemide on NKCC2.

The half-life from the dose of 40 mg furosemide was 4 hours following oral administration and 4.5 hours following intravenous administration. The terminal half-life of furosemide is approximately 2 hours following parenteral administration. The terminal half-life may be increased up to 24 hours in patients with severe renal failure.

To study the pharmacokinetics of furosemide (fursemide; Lasix) and its acyl glucuronide and to analyze the pharmacodynamic response, a study was conducted in 7 healthy subjects, mean age 34 yr, who received a single oral 80 mg dose of furosemide in tablet form. Two half-lives were distinguished in the plasma elimination of furosemide and its conjugate, with values of 1.25 and 30.4 hr for furosemide and 1.31 and 33.2 hr for the conjugate. ...

In dogs, ... the elimination half life /is/ approximately 1-1.5 hours.

Various investigators have reported a wide range of elimination half-lives for furosemide. In one study, the elimination half-life averaged about 30 minutes in healthy patients who received 20-120 mg of the drug IV. In another study, the elimination half-life averaged 9.7 hours in patients with advanced renal failure who received 1 g of furosemide IV. The elimination half-life was more prolonged in 1 patient with concomitant liver disease.

The serum half-life in therapeutic doses is 92 minutes; increasing in patients with uremia; congestive heart failure and cirrhosis as well as in the neonate and aged patients. In such patients the half-life may be extended to 20 hours.

The metabolism of furosemide occurs mainly in the kidneys and the liver, to a smaller extent. The kidneys are responsible for about 85% of total furosemide total clearance, where about 40% involves biotransformation. Two major metabolites of furosemide are furosemide glucuronide, which is pharmacologically active, and saluamine (CSA) or 4-chloro-5-sulfamoylanthranilic acid.

It would appear that frusemide glucuronide is the only or at least the major biotransformation metabolite in man. 2-amino-4- chloro-5-sulfamoylanthranilic acid has been reported in some studies but not in others; and is thought to be an analytical artifact.

In patients with normal renal function, a small amount of furosemide is metabolized in the liver to the defurfurylated derivative, 4-chloro-5-sulfamoylanthranilic acid. ...

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FUROSEMIDE

Physiologic Effects [PE] - Increased Diuresis at Loop of Henle

Established Pharmacologic Class [EPC] - Loop Diuretic

Furosemide is a Loop Diuretic. The physiologic effect of furosemide is by means of Increased Diuresis at Loop of Henle.

FUROSEMIDE

Agents that promote the excretion of urine through their effects on kidney function.

Agents that inhibit SODIUM-POTASSIUM-CHLORIDE SYMPORTERS which are concentrated in the thick ascending limb at the junction of the LOOP OF HENLE and KIDNEY TUBULES, DISTAL. They act as DIURETICS. Excess use is associated with HYPOKALEMIA and HYPERGLYCEMIA.

Following oral administration, furosemide is absorbed from the gastrointestinal tract. It displays variable bioavailability from oral dosage forms, ranging from 10 to 90%. The oral bioavailability of furosemide from oral tablets or oral solution is about 64% and 60%, respectively, of that from an intravenous injection of the drug.

The kidneys are responsible for 85% of total furosemide total clearance, where about 43% of the drug undergoes renal excretion. Significantly more furosemide is excreted in urine following the I.V. injection than after the tablet or oral solution. Approximately 50% of the furosemide load is excreted unchanged in urine, and the rest is metabolized into glucuronide in the kidney.

The volume of distribution following intravenous administration of 40 mg furosemide were 0.181 L/kg in healthy subjects and 0.140 L/kg in patients with heart failure.

Following intravenous administration of 400 mg furosemide, the plasma clearance was 1.23 mL/kg/min in patients with heart failure and 2.34 mL/kg/min in healthy subjects, respectively.

Significantly more furosemide is excreted in urine following the IV injection than after the tablet or oral solution. There are no significant differences between the two oral formulations in the amount of unchanged drug excreted in urine.

After oral administration of furosemide to 18 pregnant women on the day of delivery, substantial concentrations of the drug were detected in umbilical cord vein plasma as well as in amniotic fluid. The ratio between the furosemide concentrations in maternal vein plasma and in umbilical cord plasma increased with time and approximated unity at 8 to 10 hr after administration of the drug. The plasma half-life of furosemide appeared to be longer in the mothers than in nonpregnant healthy volunteers. In one patient the plasma level of furosemide was constant during 5 hr of observation.

Diuretics; Sodium Potassium Chloride Symporter Inhibitors

Furosemide has been used empirically and has been legally approved for many years by the US racing industry for the control of exercise-induced pulmonary haemorrhage (EIPH) or bleeding.

MEDICATION (VET)

MEDICATION

Use (kg) in Switzerland (2009): >500

(1976) 1.82X10+3 GRAMS (PRINCPL CUSTMS DISTS)

(1978) 1.25X10+6 GRAMS (PRINCPL CUSTMS DISTS)

(1976) NOT PRODUCED COMMERCIALLY IN US

(1978) NOT PRODUCED COMMERCIALLY IN US

2,4-Dichlorobenzoic acid is heated with chlorosulfonic acid, and the resulting 5-chlorosulfonyl derivative is reacted with concentrated ammonia to convert it to the 5-sulfamoyl analogue (I). Refluxing I with furfurylamine in large excess or in the presence of sodium bicarbonate yields crude furosemide, which is recrystallized from aqueous ethanol.

Produced by treatment of 2,4-dichloro-5-sulfamoylbenzoic acid with excess furfurylamine in the absence of solvent at 120-130 °C.

Preparation: K. Sturm et al., Germany patent 1122541; eidem United States of America patent 3058882 (both 1962 to Hoechst)

Prepared in 85% yield from 2-fluoro-4-chloro-5-sulfamoylbenzoic acid and furfurylamine at 95 °C for 2 hr

Animal Drugs -> FDA Approved Animal Drug Products (Green Book) -> Active Ingredients

Pharmaceuticals

The first high-ceiling diuretic on the market and is still the most important product in this group.

Furosemide use in horses for /the control of exercise-induced pulmonary haemorrhage (EIPH) or bleeding/ is highly controversial and has been criticized by organizations outside and inside of the racing industry. ... The existing literature references suggest that furosemide has the potential of increasing performance in horses without significantly changing the bleeding status.

Furosemid was on the top ten list of pharmaceuticals used in Denmark in 1995.