Frusene

Uses

Tablet: Frusemide is a diuretic recommended for use in all indications when a prompt and effective diuresis is required. Indications for Frusemide 40 mg include cardiac, pulmonary, hepatic and renal oedema, peripheral edema due to mechanical obstruction or venous insufficiency and hypertension.

Injection: Frusemide is a diuretic recommended for use when a prompt and effective diuresis is required. The intravenous formulation is appropriate for use in emergencies or when oral therapy is precluded. Indications include cardiac, pulmonary, hepatic and renal oedema.

Triamterene is a potassium-sparing diuretic used in the treatment of edema and in the management of hypertension.

Triamterene is indicated for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and the nephrotic syndrome; also in steroid-induced edema, idiopathic edema, and edema due to secondary hyperaldosteronism.

Triamterene in combination with hydrochlorothiazide is indicated for the managment of hypertension or treatment of edema in patients who develop hypokalemia following hydrochlorothiazide monotherapy, and in patients who require thiazide diuretic and in whom the development of hypokalemia cannot be risked. Triamterene allows the maintenance of potassium balance when given in combination with loop diuretics and thiazides.

Frusene is also used to associated treatment for these conditions: Acute Pulmonary Edema, Ascites, Body Fluid Retention, Edema, High Blood Pressure (Hypertension), Mild to Moderate HypertensionEdema, High Blood Pressure (Hypertension), Idiopathic Edema

How Frusene works

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.

Triamterene inhibits the epithelial sodium channels (ENaC) located on the lumenal side in the late distal convoluted tubule and collecting tubule , which are transmembrane channels that normally promotes sodium uptake and potassium secretion. In the late distal tubule to the collecting duct, sodium ions are actively reabsorbed via ENaC on the lumnial membrane and are extruded out of the cell into the peritubular medium by a sodium-potassium exchange pump, the Na-K-ATPase, with water following passively. Triamterene exerts a diuretic effect on the distal renal tubule to inhibit the reabsorption of sodium ions in exchange for potassium and hydrogen ions and its natriuretic activity is limited by the amount of sodium reaching its site of action. Its action is antagonistic to that of adrenal mineralocorticoids, such as aldosterone, but it is not an inhibitor or antagonist of aldosterone. Triamterene maintains or increases the sodium excretionm, thereby increasing the excretion of water, and reduces the excess loss of potassium, hydrogen and chloride ions by inhibiting the distal tubular exchange mechanism. Due to its diuretic effect, triamterene rapidly and reversibly reduces the lumen-negative transepithelial potential difference by almost complete abolition of Na+ conductance without altering K+ conductance. This reduces the driving force for potassium movement into the tubular lumen and thus decreases potassium excretion. Triamterene is similar in action to amiloride but, unlike amiloride, increases the urinary excretion of magnesium.

Dosage

Frusene dosage

Tablet-

Edema:

• Adults: The initial adult dose is 40 mg daily, reduced to 20 mg daily or 40 mg on alternate days. In some patients daily doses of 80 mg or higher (given in divided doses) may be required. The individually determined single dose should then be given once or twice daily (eg, at 8 am and 2 pm). For resistant edema, 80-120 mg daily. In patients with clinically severe edematous states the dose of furosemide may be carefully titrated up to 600 mg/day. When doses exceeding 80 mg/day are given for prolonged periods, careful clinical observation and laboratory monitoring are particularly advisable.
• Neonate: 0.5-2 mg/kg every 12-24 hours (every 24 hours if postmenstrual age under 31 weeks).
• Child 1 month-12 years: 0.5-2 mg/kg 2-3 times daily (every 24 hours if postmenstrual age less than 31 weeks); higher doses may be required in resistant edema; max. 12 mg/kg daily, not to exceed 80 mg daily.
• Child 12-18 years: 20-40 mg daily, increased in resistant edema to 80-120 mg daily.
• Elderly: In the elderly furosemide is generally eliminated more slowly. Dosage should be titrated until the required response is achieved.

Hypertension:

• 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. Children: The usual dose is 1-3 mg/kg body weight daily up to a maximum dose of 40 mg/day.
• Elderly: In the elderly furosemide is generally eliminated more slowly. Dosage should be titrated until the required response is achieved.

Injection-

Edema:

• Adults: Doses of 20-50 mg intramuscularly or intravenously may be given initially. If larger doses are required, they should be given increasing by 20 mg increments and not given more often than every two hours. If doses greater than 50 mg are required it is recommended that they should be given by slow intravenous infusion. The recommended maximum daily dose of furosemide administration is 1,500 mg.
• Neonate: 0.5-1 mg/kg every 12-24 hours (every 24 hours ifpostmenstrual age under 31 weeks).
• Child 1 month-12 years: 0.5-1 mg/kg repeated every 8 hours as necessary; maximum 2 mg/kg (max. 40 mg) every 8 hours.
• Child 12-18 years: 20-40 mg repeated every 8 hours as necessary; higher doses may be required in resistant cases.
• Child 1 month-18 years: By continuous intravenous infusion:0.1-2 mg/kg/hour (following cardiac surgery, initially 100 micrograms/kg/hour, doubled every 2 hours until urine output exceeds 1 mL/kg/hour).
• Elderly: In the elderly furosemide is generally eliminated more slowly. Dosage should be titrated until the required response is achieved.

Hypertension:

• Adults: Doses of 20 to 50 mg intramuscularly or intravenously may be given initially. If larger doses are required, they should be given increasing by 20 mg increments and not given more often than every two hours.
• If doses greater than 50 mg are required it is recommended that they should be given by slow intravenous infusion. The recommended maximum daily dose of furosemide administration is 1,500 mg. Children: Parenteral doses for children range from 0.5-1.5 mg/kg body weight daily up to a maximum total daily dose of 20 mg.
• Elderly: In the elderly furosemide is generally eliminated more slowly. Dosage should be titrated until the required response is achieved.

Tablet: May be taken with or without food. May be taken with meals to reduce GI discomfort.

Injection: Injection should be administered in children by slow intravenous injection

Side Effects

As with other diuretics, electrolytes and water balance may be disturbed as a result of diuresis of prolonged therapy. Prolonged use can produce alkalosis. It may also cause uric acid retention and may rarely produce acute gout. Furosemide may provoke hyperglycemia and glycosuria.

Toxicity

Clinical consequences from overdose depend on the extent of electrolyte and fluid loss and include dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia, hypochloremic alkalosis, hemoconcentration, cardiac arrhythmias (including A-V block and ventricular fibrillation). Symptoms of overdose include acute renal failure, thrombosis, delirious states, flaccid paralysis, apathy and confusion. In cirrhotic patients, overdosage might precipitate hepatic coma.

In rats, the oral LD₅₀, intraperitoneal LD₅₀, and subcutaneous LD₅₀ is 2600 mg/kg, 800 mg/kg, and 4600 mg/kg, respectively. The Lowest published toxic dose (TDLo) in a female is 6250 μg/kg.

Acute oral LD50 of triamterene in rats is 400 mg/kg and 285-380 mg/kg in mice. There has been a case of reversible acute renal failure following ingestion of 50 combination pills containing 50 mg triamterene and 25 mg hydrochlorothiazide. Symptoms of overdose, such as nausea, vomiting, gastrointestinal disturbances, weakness, and hypotension, are related to electrolyte imbalances, such as hyperkalemia. As there is no specific antidote, emesis and gastric lavage should be use to induce immediate evacuation of the stomach and careful evaluation of the electrolyte pattern and fluid balance should be made. Dialysis may be somewhat effective in case of an overdosage.

In a carciongenicity study in male and female mice administered with triamterene at the highst dosage level, there was an increased incidence of hepatocellular neoplasia, primarily adenomas. However, this was not a dose-dependent phenomenon and there was no statistically significant difference from control incidence at any dose level. In bacterial assays, there was no demonstrated mutagenic potential of triamterene. In in vitro assay using Chinese hamster ovary (CHO) cells with or without metabolic activation, there were no chromosomal aberrations. Studies evaluating the effects of triamterene on reproductive system or fertility have not been conducted. It is advised that the use of triamterene is avoided during pregnancy. As triamterene has been detected in human breast milk, triamterene should be used when nursing is ceased.

Precaution

Patients with prostatic hypertrophy or impairment of micturition have an increased risk of developing acute retention. A marked fall in blood pressure may be seen when ACE inhibitors are added to furosemide therapy. The toxic effects of nephrotoxic antibiotics may be increased by concomitant administration of potent diuretics such furosemide.

Interaction

A marked fall in blood pressure may be seen when ACE inhibitors are added to furosemide therapy. Serum lithium levels may be increased when lithium is given concomitantly with furosemide. The toxic effects of nephrotoxic antibiotics may be increased by concomitant administration of potent diuretics such as furosemide.

Volume of Distribution

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.

In a pharmacolinetic study involving healthy volunteers receiving triamterene intravenously, the volumes of distribution of the central compartment of triamterene and its hydroxylated ester metabolite were 1.49 L/kg and 0.11 L/kg, respectively. Triamterene was found to cross the placental barrier and appear in the cord blood of animals.

Elimination Route

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.

Triamterene is shown to be rapidly absorbed in the gastrointestinal tract Its onset of action achiveved within 2 to 4 hours after oral ingestion and its duration of action is 12-16 hours. It is reported that the diuretic effect of triamterene may not be observed for several days after administration. In a pharmacokinetic study, the oral bioavailability of triamterene was determined to be 52%. Following administration of a single oral dose to fasted healthy male volunteers, the mean AUC of triamterene was about 148.7 ng*hr/mL and the mean peak plasma concentrations (Cmax) were 46.4 ng/mL reached at 1.1 hour after administration. In a limited study, administration of triamterene in combination with hydrochlorothiazide resulted in an increased bioavailability of triamterene by about 67% and a delay of up to 2 hours in the absorption of the drug. It is advised that triamterene is administered after meals; in a limited study, combination use of triamterene and hydrochlorothiazide with the consumption of a high-fat meal resulted in an increase in the mean bioavailability and peak serum concentrations of triamterene and its active sulfate metabolite, as well as a delay of up to 2 hours in the absorption of the active constituents.

Half Life

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.

The half-life of the drug in plasma ranges from 1.5 to 2 hours. In a pharmacokinetic study involving healthy volunteers, the terminal half-lives for triamterene and 4′-hydroxytriamterene sulfate were 255 ± 42 and 188 ± 70 minutes, respectively, after intravenous infusion of the parent drug.

Clearance

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.

The total plasma clearance was 4.5 l/min and renal plasma clearance was 0.22 l/kg following intravenous administration of triamterene in healthy volunteers.

Elimination Route

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.

Triamterene and its metabolites are excreted by the kidney by filtration and tubular secretion. Upon oral ingestion, somewhat less than 50% of the oral dose reaches the urine. About 20% of an oral dose appears unchanged in the urine, 70% as the sulphate ester of hydroxytriamterene and 10% as free hydroxytriamterene and triamterene glucuronide.

Pregnancy & Breastfeeding use

Pregnancy Category C. Frusemide should be cautiously used in cardiogenic shock complicated by pulmonary oedema and in the first trimester of pregnancy. Blood pressure and pulse during rapid diuresis should be monitored. Caution should be observed in patients liable to electrolyte deficiency. In case of nursing mother, Frusemide may inhibit lactation because it may pass into breast milk. In that case it should be used with caution.

Contraindication

Furosemide is contraindicated in anuria, electrolyte deficiency and pre-comatose states associated with liver cirrhosis. Hypersensitivity to furosemide or sulphonamides.

Acute Overdose

Symptoms: Dehydration, electrolyte disturbances, hypotension and cardiac toxicity, hypochloremic alkalosis, hypokalaemia, blood volume reduction.

Management: Symptomatic and supportive treatment. Replacement of excessive fluid and electrolyte losses. Ensure adequate drainage in patients with urinary bladder outlet obstruction (e.g. prostatic hypertrophy). Treat hypotension with appropriate IV fluids.

Storage Condition

Store between 15-30°C. Protect from light.

Innovators Monograph

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