Furosemide + Spironolactone

Uses

Frusemide & Spironolactone combination is used for-

• Essential hypertension
• Chronic congestive heart failure
• Hepatic cirrhosis, with collection of fluid in the abdominal cavity (ascites)
• Swelling due to excess fluid retention (edema)
• Hyperaldosteronism
• Resistant edema associated with secondary hyperaldosteronism

Furosemide + Spironolactone is also used to associated treatment for these conditions: Acute Pulmonary Edema, Ascites, Body Fluid Retention, Edema, High Blood Pressure (Hypertension), Mild to Moderate HypertensionAcne, Ascites, Congestive Heart Failure (CHF), Edema, High Blood Pressure (Hypertension), Hypokalemia, Idiopathic Hirsutism, Nephrotic Syndrome, Primary Hyperaldosteronism, Secondary hyperaldosteronism, Chronic heart failure with reduced ejection fraction (NYHA Class III), Chronic heart failure with reduced ejection fraction (NYHA Class IV), Idiopathic hyperaldosteronism

How Furosemide + Spironolactone 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.

Spironolactone competitively inhibits aldosterone dependant sodium potassium exchange channels in the distal convoluted tubule. This action leads to increased sodium and water excretion, but more potassium retention. The increased excretion of water leads to diuretic and also antihypertensive effects.

Dosage

Furosemide + Spironolactone dosage

Furosemide 20 and spironolactone 50 mg: 1 to 4 tablets daily according to the patient's response.

Furosemide 40 and spironolactone 50 mg: For previously stabilized patients 1 to 2 tablets daily, orally.

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

Spironolactone may give rise to headache and drowsiness and gastrointestinal distress, including cramp and diarrhoea. Ataxia, mental confusion, and skin rashes have been reported as side effect. Gynaecomastia is not uncommon and in rare cases breast enlargement may persist. Other endocrine disorders including hirsutism, deepening of the voice, menstrual irregularities and impotence. Transient increase in blood-urea-nitrogen concentrations may occur and mild acidosis has been reported. Spironolactone may cause hyponatremia and hyperkalemia. Excessive diuresis may result in dehydration and reduction in blood volume with circulatory collapse with the possibility of vascular thrombosis and embolism particularly in elderly patients. Serious depletion of potassium and magnesium may lead to cardiac arrhythmias.

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.

Patients experiencing an overdose may present with drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Vomiting is generally induced or a gastric lavage is performed. Supportive treatment involves maintining hydration, electrolyte balance, and vital functions.

The oral LD50 in mice, rats, and rabbits is >1g/kg.

Spironolactone should be avoided in pregnancy due to reports of feminization of male fetuses in animal studies. Active metabolites of spironolactone are present in breast milk and levels that are likely inconsequential, though the long term effects have not been studied.

In animal studies, spironolactone slowed follicle development, ovulation, and implantation. Spironolactone increased the incidence of benign adenomas in the testes of male rats, benign uterine endometrial stromal polyps in female rats, and thyroid follicular cell adenomas in both sexes of rats. Spironolactone and canrenone are generally not considered to be mutagenic in tests but canrenone occasionally tests positive for mutagenicity with metabolic activation and spironolactone has occasionally tested inconclusive though slightly positive for mutagenicity.

Precaution

Caution should be taken in patients liable to electrolyte deficiency. This preparation should also be used with caution in diabetes, enlarged prostate, hypotension and in hypovolemia.

Interaction

When taken together with ACE inhibitors or potassium salts there is an increased risk of hyperkalemia. Spironolactone increases the levels of cardiac glycosides such as digoxin in the blood and this may result in digitalis toxicity. Corticosteroids may cause hypokalemia if they are used with Spironolactone. The blood pressure lowering and diuretic effects of Furosemide may be reduced or abolished when used together with indomethacin and possibly other non-steroidal anti-inflammatory drugs (NSAIDs). Furosemide may increase the ototoxicity of aminoglycoside antibiotics. Simultaneous administration of sucralfate and Furosemide may reduce the natriuretic and anti-hypertensive effect of 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.

Volume of distribution data is not readily available.

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.

Spironolactone reaches a maximum concentration in 2.6 hours and an active metabolite (canrenone) reaches a maximum concentration in 4.3 hours. When taken with food, the bioavailability of spironolactone increases to 95.4%.

Giving spironolactone with food increases the maximum concentration from 209ng/mL to 301ng/mL. The time to maximum concentration also increases from 2.28 hours to 3.05 hours. The area under the curve varies from 2103ng/mL*hr to 4544ng/mL*hr.

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.

1.4 hours.

Canrenone has a half life of 16.5 hours, 7-α-thiomethylspirolactone has a half life of 13.8 hours, and 6-ß-hydroxy-7-α-thiomethylspirolactone has a half life of 15 hours.

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.

Clearance data is not readily available.

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.

Metabolites of spironolactone are excreted 42-56% in urine, and 14.2-14.6% in the feces. No unmetabolized spironolactone is present in the urine.

Pregnancy & Breastfeeding use

Pregnancy: Spironolactone and its metabolites may cross the placental barrier. The use of spironolactone in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the mother and fetus. Animal teratology studies indicate that Furosemide may cause fetal abnormalities. Therefore, Furosemide should only be used in women in child bearing age when appropriate contraceptive measures are taken or if the potential benefits justify the potential risks to the fetus.

Lactation: Metabolites of Spironolactone have been detected in breast milk. If use of Spironolactone is considered essential, an alternative method of infant feeding should be instituted. Furosemide is excreted in breast milk and breast-feeding should be discontinued if treatment is essential.

Contraindication

Contraindicated in patients with anuria, acute renal insufficiency, rapidly deteriorating or severe impairment of renal function (creatinine clearance <30 ml/min), hyperkalaemia, Addison's disease and in patients who are hypersensitive to Spironolactone, Furosemide or sulphonamides.

Special Warning

Use in neonates: The drug is unlikely to be used in neonates.

Use in children: Spironolactone and Furosemide is not suitable for use in children. Spironolactone and Furosemide may both be excreted more slowly in the elderly.

Acute Overdose

Symptoms of overdosage include drowsiness, mental confusion, dizziness, diarrhea and vomiting etc. due to excessive diuresis. Treatment should be aimed at the replacement of fluid and correction of any electrolyte imbalance.

Storage Condition

Store at a cool and dry place, protected from light and moisture.

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