Furosemide

Furosemide is an antihypertensive agent belonging to Loop Diuretics.

Furosemide is a loop diuretic used in the treatment of hypertension and edema in congestive heart failure, liver cirrhosis, renal disease, and hypertension.

The onset of action of Furosemide is usually within the first hours of oral Furosemide intake, and it takes the first 1 to 2 hours to achieve a peak effect. The mean bioavailability of oral Furosemide is 51% compared with the bioavailability of intravenously administered Furosemide. Oral and sublingual administration of Furosemide achieves the peak concentration slower than the iv route. Although Furosemide is more avidly absorbed with a bioavailability of 59% via sublingual route compared with the oral route of administration, i.e., 47%, the half-life and time to peak concentration were not different between the oral and sublingual route of drug delivery. In healthy individuals, greater than 95% of Furosemide is bound to plasma protein, mainly albumin. Furosemide glucuronide is the major biotransformation active product of Furosemide, having an active diuretic effect. Contemporary evidence indicates that Furosemide is minimally metabolized in the liver. The terminal half-life of Furosemide is approximately 2 hours, and the total time of therapeutic effect is 6 to 8 hours. A greater extent of Furosemide is excreted in urine following the parenteral administration than oral administration.

Furosemide shows common side effects like feeling lightheaded on standing, ringing in the ears, and sensitivity to light, hypokalemia (low potassium level), hypotension (low blood pressure), and dizziness, etc.

Furosemide is available in the form of Tablet, Oral solutions and Injectable solutions.

Furosemide is available in India, China, Us, England, Netherlands, Italy and Germany.

Furosemide belonging to the Loop Diuretics, acts as an antihypertensive agent.

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 luminal 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.

The onset of action of Furosemide occurs within 30-60min (by mouth), 30min (intramuscular) and 5min (Intravenous) of its administration.

The Duration of Action for Furosemide in the body is approximately 6-8 hours (by mouth) and 2 hours (Intravenous).

The Tmax was found within 1-2 hours (by mouth) and < 15min (Intravenous) following the administration of Furosemide and the Cmax was about 100 to 400000 ng/mL.

Furosemide is available in the form of Tablet, Oral solutions and Injectable solutions.

Furosemide tablet taken by mouth. Usually once or twice a day.

Furosemide Oral solution taken by mouth as single dose either daily or on alternate day.

Furosemide Injectable solutions by Intramuscular and Intravenous as single dose or several dose.

Furosemide is a loop diuretic used to treat hypertension and edema in congestive heart failure, liver cirrhosis, renal disease, and hypertension. Furosemide promotes diuresis by blocking tubular reabsorption of sodium and chloride in the proximal and distal tubules, as well as in thick ascending loop of Henle.

Furosemide is an antihypertensive agent belonging to Loop Diuretics. Furosemide 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 luminal side into the basolateral side for reabsorption. Furosemide is a loop diuretic used to treat hypertension and edema in congestive heart failure, liver cirrhosis, renal disease, and hypertension.

Furosemide is approved for use in the following clinical indications

• Edema

Furosemide is indicated in the adults and pediatric patients for the treatment of edema associated with the congestive heart failure, cirrhosis of the liver, and renal disease, including nephrotic syndrome. Furosemide is particularly useful when an agent with greater diuretic potential is desired.

• Hypertension

Oral Furosemide may be used in adults for the treatment of hypertension alone or in combination with other antihypertensive agents. Hypertensive patients who cannot be adequately controlled with thiazides will probably also not be adequately controlled with Furosemide alone.

• Edema

Therapy should be individualized according to patient response to gain maximal therapeutic response and to determine the minimal dose needed to maintain that response.

Adults

The usual initial dose of Furosemide is 20 to 80 mg given as a single dose. Ordinarily a prompt diuresis ensues. If needed, the same dose can be administered 6 to 8 hours later or the dose may be increased. The dose may be raised by 20 or 40 mg and given not sooner than 6 to 8 hours after the previous dose until the desired diuretic effect has been obtained. The individually determined single dose should then be given once or twice daily (eg, at 8 am and 2 pm). The dose of Furosemide may be carefully titrated up to 600 mg/day in patients with clinically severe edematous states.

Edema may be most efficiently and safely mobilized by giving Furosemide on 2 to 4 consecutive days each week.

When doses exceeding 80 mg/day are given for prolonged periods, careful clinical observation and laboratory monitoring are particularly advisable.

Geriatric patients

In general, dose selection for the elderly patient should be cautious, usually starting at the low end of the dosing range.

Pediatric patients

The usual initial dose of oral Furosemide in pediatric patients is 2 mg/kg body weight, given as a single dose. If the diuretic response is not satisfactory after the initial dose, dosage may be increased by 1 or 2 mg/kg no sooner than 6 to 8 hours after the previous dose. Doses greater than 6 mg/kg body weight are not recommended. For maintenance therapy in pediatric patients, the dose should be adjusted to the minimum effective level.

• Hypertension

Therapy should be individualized according to the patient's response to gain maximal therapeutic response and to determine the minimal dose needed to maintain the therapeutic response.

Adults

The usual initial dose of Furosemide for hypertension is 80 mg, usually divided into 40 mg twice a day. Dosage should then be adjusted according to response. If response is not satisfactory, add other antihypertensive agents.

Changes in blood pressure must be carefully monitored when Furosemide is used with other antihypertensive drugs, especially during initial therapy. To prevent excessive drop in blood pressure, the dosage of other agents should be reduced by at least 50 percent when Furosemide is added to the regimen. As the blood pressure falls under the potentiating effect of Furosemide, a further reduction in dosage or even discontinuation of other antihypertensive drugs may be necessary.

Geriatric Patients

In general, dose selection and dose adjustment for the elderly patient should be cautious, usually starting at the low end of the dosing range.

Furosemide is available in various strengths as Tablets (20mg, 40mg and 80mg), Oral solution (10mg/mL and 8mg/mL) and Injectable solution (10mg/mL).

Sodium Rich Food: Avoid consumption of a high-salt or high-sodium diet while taking Furosemide.

Furosemide is contraindicated in 

• Patients with anuria
• Patients with the history of hypersensitivity to Furosemide.

• Hepatic cirrhosis and ascites

In patients with hepatic cirrhosis and ascites, Furosemide therapy is best initiated in the hospital. In hepatic coma and in states of electrolyte depletion, therapy should not be instituted until the basic condition is improved. Sudden alterations of fluid and electrolyte balance in patients with cirrhosis may precipitate hepatic coma; therefore, strict observation is necessary during the period of diuresis. Supplemental potassium chloride and, if required, an aldosterone antagonist are helpful in preventing hypokalemia and metabolic alkalosis.

• Progressive renal disease

If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, Furosemide should be discontinued.

• Hearing impairment and deafness

Cases of tinnitus and reversible or irreversible hearing impairment and deafness have been reported. Reports usually indicate that Furosemide ototoxicity is associated with rapid injection, severe renal impairment, the use of higher than recommended doses, hypoproteinemia or concomitant therapy with aminoglycoside antibiotics, ethacrynic acid, or other ototoxic drugs. If the physician elects to use high dose parenteral therapy, controlled intravenous infusion is advisable (for adults, an infusion rate not exceeding 4 mg Furosemide per minute has been used).

• Hypotension

Patients receiving Furosemide should be advised that they may experience symptoms from excessive fluid and/or electrolyte losses. The postural hypotension that sometimes occurs can usually be managed by getting up slowly. Potassium supplements and/or dietary measures may be needed to control or avoid hypokalemia.

• Patients with diabetes mellitus

Patients with diabetes mellitus should be told that Furosemide may increase blood glucose levels and thereby affect urine glucose tests. The skin of some patients may be more sensitive to the effects of sunlight while taking Furosemide.

• Acute kidney injury

Furosemide causes greater loss of water than sodium loss, resulting in the production of hypotonic urine. Furosemide should be discontinued.

Consumption of alcohol is not recommended while you are taking this medicine due to increased risk of severe adverse effects. These side effects may include dizziness and fainting.

This medicine is not recommended for use in breastfeeding women unless absolutely necessary. Because it appears in breast milk, caution should be exercised when Furosemide is administered to a nursing mother. Furosemide may inhibit lactation. Physician may prescribe a safer alternative based on your clinical condition.

Furosemide is known to cross the placenta, and animal reproduction studies have shown adverse events. Although pregnant women with heart failure have had treatment with Furosemide, a risk and benefits discussion should occur with the pregnant patient, and caution is necessary with the decision to take Furosemide during pregnancy; fetal growth will require close monitoring.

Sodium Rich Food: Avoid consumption of a high-salt or high-sodium diet while taking Furosemide.

The adverse reactions related to Furosemide can be categorized as

Common Adverse effects

• Muscle cramps
• Nausea
• Rash
• Restlessness
• Increased Urinary frequency
• Urticaria
• Vertigo
• Weakness
• Diarrhea
• Dizziness
• Headache

Less Common Adverse effects

• Hyperuricemia (40%)
• Hypokalemia
• Hypocalcemia
• Tinnitus
• Hypomagnesemia
• Hypotension
• Stevens-Johnson Syndrome
• erythema multiforme
• exanthematous pustulosis
• exfoliative dermatitis
• bullous pemphigoid purpura
• pruritus

• Lithium

Lithium generally should not be given with diuretics because they reduce lithium's renal clearance and add a high risk of lithium toxicity.

• Angiotensin converting enzyme inhibitors or angiotensin II receptor blockers

Furosemide combined with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers may lead to severe hypotension and deterioration in renal function, including renal failure. An interruption or reduction in the dosage of Furosemide, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers may be necessary.

• Norepinephrine

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

• Sucralfate

Simultaneous administration of sucralfate and Furosemide tablets may reduce the natriuretic and antihypertensive effects of Furosemide. Patients receiving both drugs should be observed closely to determine if the desired diuretic and/or antihypertensive effect of Furosemide is achieved. The intake of Furosemide and sucralfate should be separated by at least two hours.

• Chloral hydrate

In isolated cases, intravenous administration of Furosemide within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of Furosemide concomitantly with chloral hydrate is therefore not recommended.

• Phenytoin

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

• Tubocurarine

Furosemide has a tendency to antagonize the skeletal muscle relaxing effect of tubocurarine and may potentiate the action of succinylcholine.

• Cisplatin

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

The common side of Furosemide include the following

Common

• Headache
• Weakness
• Muscle spasm
• Dizziness
• Electrolyte imbalance
• Blurred vision
• Dehydration
• Increased urination frequency
• Low blood pressure

Rare

• Hearing impairment
• Increased sensitivity of the skin to sunlight
• Skin rash

• Pregnancy

Pregnancy category C

Furosemide has been shown to cause the unexplained maternal deaths and abortions in rabbits at 2, 4 and 8 times maximal recommended human dose. There are no adequate and well-controlled studies in the pregnant women. Furosemide should be used during pregnancy only if potential benefit justifies the potential risk to the fetus. Treatment during pregnancy requires monitoring of fetal growth because of the potential for higher birth weights. The effects of Furosemide on embryonic and fetal development and on pregnant dams were studied in mice, rats and rabbits. Furosemide caused unexplained maternal deaths and abortions in the rabbit at the lowest dose of 25 mg/kg (2 times the maximal recommended human dose of 600 mg/day). In another study, a dose of 50 mg/kg (4 times the maximal recommended human dose of 600 mg/day) also caused maternal deaths and abortions when administered to rabbits between Days 12 and 17 of gestation. In a third study, none of the pregnant rabbits survived a dose of 100 mg/kg. Data from the above studies indicate fetal lethality that can precede maternal deaths. The results of the mouse study and one of the three rabbit studies also showed an increased incidence and severity of hydronephrosis (distention of the renal pelvis and, in some cases, of the ureters) in fetuses derived from the treated dams as compared with the incidence in fetuses from the control group.

• Nursing Mothers

Because it appears in breast milk, caution should be exercised when Furosemide is administered to a nursing mother. Furosemide may inhibit lactation.

• Pediatric Use

In premature infants Furosemide may precipitate nephrocalcinosis/nephrolithiasis. Nephrocalcinosis/nephrolithiasis has also been observed in children under 4 years of age with no history of prematurity who have been treated chronically with FUROSEMIDE. Monitor renal function, and renal ultrasonography should be considered, in pediatric patients receiving Furosemide. If Furosemide is administered to premature infants during the first weeks of life, it may increase the risk of persistence of patent ductus arteriosus

• Geriatric Use

Controlled clinical studies of Furosemide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for the elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.

• The principal signs and symptoms of overdose with Furosemide are dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and are extensions of its diuretic action.
• The acute toxicity of Furosemide has been determined in mice, rats and dogs. In all three, the oral LD50 exceeded 1000 mg/kg body weight, while the intravenous LD50 ranged from 300 to 680 mg/kg. The acute intragastric toxicity in neonatal rats is 7 to 10 times that of adult rats.
• The concentration of Furosemide in biological fluids associated with toxicity or death is not known. Treatment of overdosage is supportive and consists of replacement of excessive fluid and electrolyte losses. Serum electrolytes, carbon dioxide level and blood pressure should be determined frequently. Adequate drainage must be assured in patients with urinary bladder outlet obstruction (such as prostatic hypertrophy).
• Hemodialysis does not accelerate Furosemide elimination.

Pharmacodynamic

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

Pharmacokinetics

• Absorption

The onset of action of Furosemide is usually within the first hour of oral Furosemide intake, and it takes the first 1 to 2 hours to achieve a peak effect. The mean bioavailability of oral Furosemide is 51% compared with the bioavailability of intravenously administered Furosemide. Bioavailability: The Furosemide absorption is slower than normal in patients with edema, particularly in patients with decompensated heart failure; however, the amount of loop diuretic absorbed is normal. Oral and sublingual administration of Furosemide achieves a peak concentration slower than the iv route. Although Furosemide is more avidly absorbed with a bioavailability of 59% via the sublingual route compared with the oral route of administration, i.e., 47%, the half-life and time to peak concentration were not different between the oral and sublingual route of drug delivery.

• Distribution
  

In healthy individuals, greater than 95% of Furosemide is bound to plasma protein, mainly albumin. Only 2.3% to 4.1% of Furosemide is existent in an unbound form in therapeutic concentrations.

• Metabolism

Furosemide glucuronide is a major biotransformation active product of Furosemide, having an active diuretic effect. Contemporary evidence indicates that Furosemide is minimally metabolized in the liver.

• Excretion
  

The terminal half-life of Furosemide is approximately 2 hours, and the total time of therapeutic effect is 6 to 8 hours. However, the half-life of Furosemide will prolong in patients with chronic renal disease. Although more Furosemide gets excreted in the urine after IV administration, there is no difference in the amount of unchanged Furosemide excretion in urine between the two formulations. After intravenous administration, Furosemide achieves an early and high serum peak concentration and a higher peak excretion rate. A greater extent of Furosemide is excreted in urine following the parenteral administration than oral administration.