FUROSEMIDE

Chemistry - A loop diuretic related structurally to the sulfonamides, furosemide occurs as anodorless, practically tasteless, white to slightly yellow, fine, crystalline powder. Furosemide has amelting point between 203° - 205° with decomposition, and a pKa of 3.9. It is practically insolublein water, sparingly soluble in alcohol and freely soluble in alkaline hydroxides. The injectableproduct has its pH adjusted to 8 - 9.3 with sodium hydroxide. Furosemide may also be known asfrusemide.

Storage, Stability, Compatibility

Furosemide tablets should be stored in light-resistant, well-closed containers. The oral solution should be stored at room temperature and protected from light and freezing. Furosemide injection should be stored at room temperature. A precipitate may form ifthe injection is refrigerated, but will resolubolize when warmed without alteration in potency. Thehuman injection (10 mg/ml) should not be used if it is a yellow-color. The veterinary injection (50mg/ml) normally has a slight yellow color. Furosemide is unstable at an acid pH, but is very stableunder alkaline conditions.
Furosemide injection (10 mg/ml) is reportedly compatible with all commonly used intravenoussolutions and the following drugs: amikacin sulfate, cimetidine HCl, kanamycin sulfate, tobramycinsulfate and verapamil.
It is reportedly incompatible with the following agents: ascorbic acid solutions, dobutamine HCl, epinephrine, gentamicin sulfate, netilmicin sulfate and tetracylines. It should generally not be mixedwith antihistamines, local anesthetics, alkaloids, hypnotics, or opiates.

Pharmacology - FUROSEMIDE

Furosemide reduces the absorption of electrolytes in the ascending section of theloop of Henle, decreases the reabsorption of both sodium and chloride and increases the excretionof potassium in the distal renal tubule, and directly effects electrolyte transport in the proximaltubule. The exact mechanisms of furosemide's effects have not been established. It has no effect oncarbonic anhydrase nor does it antagonize aldosterone.
Furosemide increases renal excretion of water, sodium, potassium, chloride, calcium, magnesium, hydrogen, ammonium, and bicarbonate. It causes some renal venodilation and transiently increasesglomerular filtration rates (GFR). Renal blood flow is increased and decreased peripheral resistancemay occur. Furosemide can cause hyperglycemia, but to a lesser extent than the thiazides.
Uses, Indications - Furosemide is used for its diuretic activity in all species. It is used in smallanimals for the treatment of congestive cardiomyopathy, pulmonary edema, hypercalcuricnephropathy, uremia, as adjunctive therapy in hyperkalemia and, occasionally, as an antihypertensiveagent. In cattle, it is approved for use for the treatment of post-parturient udder edema. It has beenused to help prevent or reduce epistaxis (exercise-induced pulmonary hemorrhage; EIPH) in racehorses.

Pharmacokinetics - FUROSEMIDE

The pharmacokinetics of furosemide have been studied in a limited fashion indomestic animals. In dogs, the oral bioavailability is approximately 77% and the elimination half-life approximately 1 - 1.5 hours.
In humans, furosemide is 60-75% absorbed following oral administration. The diuretic effecttakes place within 5 minutes after IV administration and within one hour after oral dosing. Peakeffects occur approximately 30 minutes after IV dosing, and 1-2 hours after oral dosing. The drugis approximately 95% bound to plasma proteins in both azotemic and normal patients. The serumhalf-life is about 2 hours, but is prolonged in patients with renal failure, uremia, CHF, and inneonates.
Contraindications/Precautions - Furosemide is contraindicated in patients with anuria or whoare hypersensitive to the drug. The manufacturer states that the drug should be discontinued inpatients with progressive renal disease if increasing azotemia and oliguria occur during therapy.
Furosemide should be used with caution in patients with preexisting electrolyte or water balanceabnormalities, impaired hepatic function (may precipitate hepatic coma) and diabetetes mellitus.
Patients with conditions that may lead to electrolyte or water balance abnormalities (e.g., vomiting, diarrhea, etc.) should be monitored carefully. Patients hypersensitive to sulfonamides may also behypersensitive to furosemide (not documented in veterinary species).

Adverse Effects, Warnings

Furosemide may induce fluid and electrolyte abnormalities. Patientsshould be monitored for hydration status and electrolyte imbalances (especially potassium, calciumand sodium). Other potential adverse effects include ototoxicity (especially in cats with high dose IV therapy), gastrointestinal disturbances, hematologic effects (anemia, leukopenia), weakness andrestlessness.
Overdosage - The LD50 in dogs after oral administration is > 1000 mg/kg and after IV injection >300 mg/kg. Chronic overdosing at 10 mg/kg for six months in dogs led to development of calcification and scarring of the renal parenchyma.
Acute overdosage may cause electrolyte and water balance problems, CNS effects (lethargy tocoma and seizures) and cardiovascular collapse.
Treatment consists of emptying the gut after recent oral ingestion, using standard protocols. Avoidgiving concomitant cathartics as they may exacerbate the fluid and electrolyte imbalances that canoccur. Aggressively monitor and treat electrolyte and water balance abnormalities supportively.
Additional y, monitor respiratory, CNS, and cardiovascular status. Treat supportively andsymptomatically if necessary.

Drug Interactions

Pharmacologic effects of theophylline may be enhanced when given withfurosemide.
Ototoxicity and nephrotoxicity associated with the aminoglycoside antibiotics may be increasedwhen furosemide is also used.
If used concomitantly with corticosteroids, corticotropin or amphotericin B, furosemide mayincrease the chance of hypokalemia development. Furosemide-induced hypokalemia may increasechances of digitalis toxicity.
Patients on aspirin therapy may need dosage adjustment as furosemide competes for renal excretory sites.
Furosemide may inhibit the muscle relaxation qualities of tubocurarine, but increase the effectsof succinylcholine.
Enhanced effects may occur if furosemide is used concomitantly with other diuretics.
The uricosuric effects of probenecid or sulfinpyrazone may be inhibited by furosemide.
Furosemide may alter the requirements of insulin or other anti-diabetic agents in diabetic patients.