Action And Clinical Pharmacology: Spironolactone is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent, sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium loss is minimized. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents which act more proximally in the renal tubule.
Increased levels of the mineralocorticoid, aldosterone, are present in primary and secondary hyperaldosteronism. Edematous states in which secondary aldosteronism is usually involved include congestive heart failure, hepatic cirrhosis, and nephrotic syndrome. By competing with aldosterone for receptor sites, spironolactone provides effective therapy for the edema and ascites in those conditions. Spironolactone counteracts secondary aldosteronism induced by the volume depletion and associated sodium loss caused by diuretic therapy.
Spironolactone is effective in lowering the systolic and diastolic blood pressure in patients with primary hyperaldosteronism. It is also effective in most cases of essential hypertension, despite the fact that aldosterone secretion may be within normal limits in benign essential hypertension.
Through its action in antagonizing the effect of aldosterone, spironolactone inhibits the exchange of sodium for potassium in the distal renal tubule and helps to prevent potassium loss.
Spironolactone has not been demonstrated to elevate serum uric acid, to precipitate gout, or to alter carbohydrate metabolism.
Spironolactone is rapidly and extensively metabolized. Sulfur-containing products are the predominant metabolites and are thought to be primarily responsible for the therapeutic effects of the drug. Approximately 25 to 30% of the dose administered is converted to canrenone, which attains peak serum levels 2 to 4 hours after single oral administration of spironolactone. In the dose range of 25 to 200 mg, an approximately linear relationship exists between a single dose of spironolactone and plasma levels of canrenone.
Plasma concentrations of canrenone decline in 2 distinct phases, the first phase lasting from 3 to 12 hours, being more rapid than the second phase lasting from 12 to 96 hours. Canrenone clearance data, following multiple doses of spironolactone, indicate that accumulation of canrenone in the body with 100 mg once a day would be lower than with 25 mg 4 times a day. Both spironolactone and canrenone are more than 90% bound to plasma proteins. The metabolites of spironolactone are excreted both in the urine (32 to 53%), and through biliary excretion in the feces (14 to 36%).
Indications And Clinical Uses: Primary Hyperaldosteronism: A useful agent in the diagnosis of primary hyperaldosteronism. In the presence of hypokalemic alkalosis and hypertension, a diagnosis of primary hyperaldosteronism should be considered if both blood pressure and serum electrolytes return to normal following treatment with spironolactone.
Spironolactone is useful in the preoperative treatment of patients with primary hyperaldosteronism and for the maintenance therapy of such patients who decline surgery, or who are unsuitable for surgery.
Edematous Conditions: Congestive Heart Failure (CHF): Spironolactone is useful in the management of edema and sodium retention in CHF when the patient is only partially responsive to, or intolerant of, other therapeutic measures. Spironolactone may be used alone or with thiazides. It is indicated in patients with CHF taking digitalis when other therapies are considered inappropriate.
Cirrhosis of the Liver Accompanied by Edema and/or Ascites: Aldosterone levels may be exceptionally high in this condition. Spironolactone is indicated for maintenance therapy, in combination with bed rest and the restriction of fluid and sodium.
Nephrotic Syndrome: Spironolactone is useful for inducing a diuresis in patients not responsive to glucocorticoid therapy (for the nephrotic syndrome), and not responding to other diuretics. However, spironolactone has not been shown to affect the basic pathological process.
Essential Hypertension: Spironolactone is indicated, usually in combination with other drugs, for patients who cannot be treated adequately with other agents or for whom other agents are considered inappropriate. Spironolactone alone has mild to moderate antihypertensive activity.
Hypokalemia: Spironolactone is indicated for treatment of hypokalemia when other measures are considered inappropriate or inadequate. It is also indicated for the prophylaxis of hypokalemia in digitalis therapy when other measures are inadequate or inappropriate.
Contra-Indications: Anuria, acute renal insufficiency, significant impairment of renal function, hyperkalemia, and sensitivity to spironolactone.
Manufacturers’ Warnings In Clinical States: Potassium (K Supplementation: Do not give potassium supplementation (including dietary potassium) in conjunction with spironolactone therapy. Excessive potassium intake may cause hyperkalemia in patients receiving spironolactone. Do not administer spironolactone concurrently with other potassium sparing diuretics.
Turmorigenicity: Spironolactone, in chronic toxicity studies, has been shown to be a tumorigen in rats.
Use spironolactone only for conditions described under Indications.
Precautions: Electrolyte Balance: Because of the diuretic action of spironolactone, patients should be carefully evaluated for possible disturbance of fluid and electrolyte balance.
Hyperkalemia: Hyperkalemia may occur in patients treated with spironolactone if the potassium intake is excessive. This can cause cardiac irregularities, some of which may be fatal. Hyperkalemia may also occur even in the absence of potassium supplementation, particularly in patients with impaired renal function, elderly patients, or patients with diabetes. Consequently, no potassium supplementation should ordinarily be given with spironolactone. Hyperkalemia can be treated promptly by rapid i.v. administration of glucose (20 to 50%) and regular insulin, using 0.25 to 0.5 units of insulin/g of glucose. This is a temporary measure to be repeated if required. Spironolactone should be discontinued and potassium intake (including dietary potassium) restricted.
Hyponatremia: During the administration of spironolactone, patients suffering from sodium depletion must be attentively monitored and signs of electrolyte imbalance must be carefully checked.
Spironolactone may, if administered concomitantly with other diuretics, cause or aggravate hyponatremia, as manifested by dryness of the mouth, thirst, lethargy, and drowsiness.
Metabolic Effects: Hyperchloremic metabolic acidosis: Spironolactone may induce or worsen hyperchloremic metabolic acidosis.
Acidosis and Renal Function: Rare reports of acidosis have been reported with spironolactone.
Drug Interactions: Diuretics and Antihypertensives: Although spironolactone may be administered concomitantly with diuretics and antihypertensives, the effect of spironolactone is additive. Thus, it is advisable to reduce the dose of these drugs. In particular, the dose of ganglionic blocking agents should be reduced by at least 50% when spironolactone is added to the regimen.
Hyperkalemia has been associated with the use of angiotensin converting enzyme (ACE) inhibitors in combination with potassium-sparing diuretics.
Norepinephrine: Spironolactone reduces the vascular responsiveness to norepinephrine. Caution should be exercised in the management of patients subjected to regional or general anesthesia.
Digoxin: Spironolactone has been shown to increase the half-life of digoxin. This may result in increased serum digoxin levels and subsequent digitalis toxicity. It may be necessary to reduce the maintenance dose of digoxin when spironolactone is administered, and the patient should be carefully monitored to avoid over- or underdigitalization.
Carbenoxolone: Carbenoxolone may cause sodium retention and thus decrease the effectiveness of spironolactone. Concurrent use of the two agents should be avoided.
Nonsteroidal Anti-inflammatory Drugs: Although it has been reported that ASA, mefenamic acid, and indomethacin may interfere with the diuretic action of spironolactone, due to inhibition of intrarenal synthesis of prostaglandins, it has been shown that ASA does not alter the effect of spironolactone on blood pressure, serum electrolytes, urea nitrogen, or plasma renin activity in hypertensive patients.
Hyperkalemia has been associated with the use of indomethacin in combination with potassium-sparing diuretics.
Gynecomastia: Gynecomastia may develop with the use of spironolactone and physicians should be advised of its possible occurrence. The development of gynecomastia appears to be related to both dosage and duration of therapy and is normally reversible when the drug is discontinued. If gynecomastia develops, discontinue the drug. In rare instances some breast enlargement may persist.
Management of Cirrhosis: Although high doses of spironolactone are required to treat edema and ascites in patients with cirrhosis, the drug dosage may be decreased before diuresis is complete to avoid the possibility of dehydration.
Pregnancy and Lactation: Spironolactone and its metabolites may cross the placental barrier. Therefore, the use of spironolactone requires that the potential benefits be weighed against the possible hazard to the mother and fetus. In rats, feminization of the fetus has been reported at high doses. Canrenone, a metabolite of spironolactone, appears in breast milk. If use of the drug is deemed essential, an alternative method of infant feeding should be instituted.
Laboratory Tests: General: Spironolactone therapy may cause transient elevation of BUN, especially in patients with pre-existing renal impairment.
Several reports of possible interference with digoxin radioimmunoassays by spironolactone or its metabolites have appeared in the literature. Neither the extent nor the potential clinical significance of this interference (which may be assay-specific) has been fully established.
Discontinue spironolactone for at least 4, and preferably 7 days prior to plasma cortisol determinations, if they are to be done by the method of Mattingly, that is, by fluorometric assay. No interference has been demonstrated with the competitive protein binding technique or radioimmunoassay technique.
Adrenal Vein Catheterization and Plasma Renin Activity: Discontinue spironolactone several days prior to adrenal vein catheterization for measurement of aldosterone concentrations and measurements of plasma renin activity.
Adverse Reactions: Gynecomastia is observed not infrequently. In rare instances, gynecomastia may persist. Other adverse effects that have been reported in association with spironolactone are: gastrointestinal symptoms (including nausea, vomiting, cramping, diarrhea, gastric bleeding, gastritis and ulceration), drowsiness, lethargy, headache, maculopapular or erythematous cutaneous eruptions, urticaria, mental confusion, drug fever, ataxia, inability to achieve or maintain erection, impotence, abnormal semen (decreased motility and sperm count), irregular menses or amenorrhea and postmenopausal bleeding. Carcinoma of the breast has been reported in patients taking spironolactone, but a cause and effect relationship has not been established. A few cases of agranulocytosis have been reported in patients taking spironolactone.
Adverse reactions are usually reversible upon discontinuation of the drug.
Symptoms And Treatment Of Overdose: Symptoms: There have been no reports of fatal overdose in man (except indirectly through hyperkalemia). Nausea and vomiting occur and (much more rarely) drowsiness, mental confusion, diarrhea, or a maculopapular or erythematous rash. These manifestations disappear promptly on discontinuation of medication. Hyperkalemia may be exacerbated.
Treatment: No specific antidote. No persistent toxicity has occurred or is expected. Appearance of effects described above require only discontinuance of the drug. Induce vomiting and evacuate the stomach by lavage. For hyperkalemia, discontinue spironolactone, reduce potassium intake, consider administration of potassium excreting diuretics, i.v. glucose with regular insulin (see Precautions), ion exchange resins, or dialysis. Treat fluid depletion and electrolyte imbalances appropriately if present.
Dosage And Administration: Diagnosis and Treatment of Primary Hyperaldosteronism: As an initial diagnostic measure to provide presumptive evidence of primary hyperaldosteronism while patients are on normal diets.
Long Test: Administer 400 mg/day for 3 to 4 weeks. Correction of hypokalemia and hypertension provides presumptive evidence for the diagnosis of primary hyperaldosteronism.
Short Test: Administer 400 mg/day for 4 days. If serum potassium increases or urinary potassium decreases during spironolactone administration, but reverts when spironolactone is discontinued, a presumptive diagnosis of primary hyperaldosteronism should be considered.
After the diagnosis of primary hyperaldosteronism has been established by more definitive testing procedures, spironolactone may be administered in doses of 75 to 400 mg/day in preparation for surgery. For those unsuitable for surgery, spironolactone may be employed for long-term maintenance therapy at the lowest effective dosage determined for the individual.
Edematous Disorders Associated with Congestive Heart Failure, Cirrhosis and the Nephrotic Syndrome: When given as the sole agent for diuresis, continue administration for at least 5 days. If an adequate response has been achieved within 5 days, continue dosage at the same level (or in selected patients, at a reduced dosage) in either single or divided daily doses. Some may respond adequately to a dosage of only 75 mg daily. If adequate diuresis is not obtained within 5 days, a second diuretic also should be given for additive effect. Occasionally for severe, resistant edema, one may add a potent glucocorticoid to this combined therapy. Normally, an initial daily dosage of 100 mg (but may range from 25 to 200 mg/day) of spironolactone administered in either single or divided doses is recommended.
Children: The initial daily dosage should provide approximately 3 mg/kg of body weight administered in either single or divided doses. This dose should be reduced to 1 to 2 mg/kg for maintenance therapy or combination use with other diuretics.
Essential Hypertension: Usually in combination with other drugs, spironolactone is indicated for patients who cannot be treated adequately with other agents or for whom other agents are considered inappropriate. Spironolactone has mild to moderate antihypertensive activity.
Adults: Initial daily dosage: 50 to 100 mg/day (in either single or divided doses) of spironolactone is recommended. Spironolactone may also be given with diuretics that act more proximally in the renal tubule or with other antihypertensive agents. Since a stabilized response may not occur before 2 weeks, continue treatment in either single or divided daily doses for that duration of time. Subsequently, adjust dosage in response to patient’s needs. Most patients will respond to doses not exceeding 200 mg/day.
Hypokalemia: Ranging from 25 to 100 mg/day is useful in treating a diuretic-induced hypokalemia, when oral potassium supplements or other potassium-sparing regimens are inappropriate.
Availability And Storage: 25 mg: Each white to off-white, round, standard, biconvex tablet, 8.7 mm diameter impressed on one side, the other side plain and with peppermint aroma, contains: spironolactone 25 mg. Nonmedicinal ingredients: calcium sulfate, cornstarch, magnesium stearate, peppermint flavoring and povidone. Bottles of 250. Store below 30°C.
100 mg: Each white to off-white, round, standard, biconvex tablet, 11.1 mm diameter impressed ¼ on one side, the other side plain and with peppermint aroma, contains: spironolactone 100 mg. Nonmedicinal ingredients: calcium sulfate, cornstarch, magnesium stearate, peppermint flavoring and povidone. Bottles of 100. Store below 30°C.
ALDACTONE ® Searle Spironolactone Aldosterone Antagonist