Spironolactone - A Comprehensive Review

Overview:

Spironolactone is practically not soluble in water, soluble in alcohol, and freely soluble in chloroform and benzene. Spironolactone is a medication used in the treatment and management of hypertension and heart failure with a few indications aside from cardiovascular disease. It comes under the mineralocorticoid receptor antagonist class of drugs. This activity reviews the actions, indications, and contraindications for Spironolactone as a valuable agent in the management of cardiovascular diseases and other disorders when applicable. Spironolactone was originally developed purely for this ability before other pharmacodynamic properties of the drug were discovered. It is indicated to treat several conditions, including heart failure, hyperaldosteronism, adrenal hyperplasia, hypertension, and nephrotic syndrome. Off-label and labeled uses of Spironolactone involving its anti-androgenic activity include hirsutism, female pattern hair loss, and adult acne vulgaris. Spironolactone is also frequently used in medical gender transition.

How Does Spironolactone Work?

This drug belongs to a group of drugs called aldosterone antagonists (blockers) or potassium-sparing diuretics. These drugs are often used to treat similar conditions. Spironolactone works by blocking aldosterone (a chemical made by the body that causes water retention) activity. This makes certain heart, kidney, and liver conditions worse. By blocking aldosterone, the body will not retain fluid. This process also stops the body from ridding itself of potassium. This drug may lower blood pressure by blocking aldosterone’s effect on the blood vessels.

How Is Spironolactone Used?

Spironolactone comes as a tablet and suspension to be taken orally. It is generally taken once or twice a day. Spironolactone suspension has to be taken without fail, either with food or without food each time. Spironolactone has to be taken at around the same time(s) every day. Follow all the directions on the prescription label carefully, and the pharmacist or doctor should be asked to explain whatever is not understood. Spironolactone has to be taken exactly as directed. It should not be taken in more or less quantity or more often than prescribed by the doctor.

The doctor may start on a low dose of Spironolactone and gradually increase the dose depending on the individual's needs. Spironolactone tablets and suspensions release the medication uniquely in the body and cannot be replaced by one another. Do not switch to a different Spironolactone product without the doctor's advice. It may take about two weeks or longer before the full effect of Spironolactone occurs. Spironolactone should be taken continuously even if the patient feels well.

Dosage:

Hypertension:

• Adult (18 Years to 64 Years): The usual starting dosage is 25 mg to 100 mg, taken orally each day. It is given as a single dose or split into two.

• Child Dosage (0 to 17 Years): This medication is not authorized for use in children younger than 18 years of age.

• Older Adult Dosage (65 Years or More Than That): There are no specific recommendations for dosing older adults. Older adults might process drugs more at a lower speed. A typical adult dose may cause levels of this drug to be more elevated than typical in the body. If the patient is an older adult, then they may need a lower dose or a different dosage schedule.

Dosage Form:

Spironolactone is available in tablet and suspension forms. Either form has a different medical effect and thus cannot be interchanged.

The Direction of Administration:

Spironolactone is used for long-term treatment. It causes serious risks if not taken as it is prescribed. The tablets or suspensions have to be taken by mouth with or without food. The patient may need to check the blood pressure using a blood pressure monitor. The patient should keep a log with the date, time of day, and blood pressure readings. These logs are supposed to be brought to the doctor's appointments.

Warnings:

• Spironolactone may cause hyperkalemia in patients. (Hyperkalemia, a condition in which plasma potassium or serum level is above the upper limits of normal).

• Excessive diuresis can cause hypotension (low blood pressure), symptomatic dehydration, and worsening renal function in salt-depleted patients, particularly those taking angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers.

• Spironolactone has the potential to cause hypomagnesemia (an electrolyte disturbance caused by a low serum magnesium level), hyponatremia (a serum sodium concentration of less than normal), hypocalcemia (happens when the levels of calcium in the blood are too low), hypochloremic alkalosis (results from either low chloride intake or excessive chloride wasting), and hyperglycemia (high blood sugar level).

• Gynecomastia can be caused by Spironolactone. (Gynecomastia is a condition that causes male breasts to swell and become larger than normal).

For Patients:

What Is Hypertension?

High blood pressure is a common condition that affects the arteries of the body. It is also named hypertension. If a person has high blood pressure, the blood's force pushing against the walls of the arteries is consistently too high. In this condition, the heart has to work harder to pump blood. Blood pressure higher than 180/120 mm Hg is a hypertensive emergency. Untreated high blood pressure increases the risk of heart attack, stroke, and many other serious health concerns.

Things to Consider:

Before Taking Spironolactone:

• The doctor and pharmacist should be informed if the patient is allergic to Spironolactone, any other medications, or any of the tablet ingredients. Ask the pharmacist for a list of the ingredients.

• The doctor has to be notified if the patient is taking Eplerenone. The doctor may tell the person not to take Spironolactone if the patient is taking this medication.

• The doctor and pharmacist have to be informed about what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products the person is taking or plans to take.

• The doctor has to be informed if the person has Addison's disease or other conditions that can cause high blood levels of potassium or kidney disease. The doctor may tell the patient not to take Spironolactone.

• Inform the doctor if the patient has any liver disease, or the patient is pregnant, or plans to become pregnant, or is breastfeeding. If the patient becomes pregnant while taking Spironolactone, call the doctor.

• If the patient is having surgery, including dental surgery, the doctor or dentist should be informed that the patient is taking Spironolactone.

• The patient must know that drinking alcohol with this medication can cause lightheadedness, dizziness, and fainting if the person gets up too quickly from a lying position. The doctor should know about drinking alcohol if the person is taking Spironolactone.

What Side-Effects Spironolactone Can Cause?

Following are some of the side effects caused by Spironolactone:

• Vomiting.

• Drowsiness.

• Diarrhea.

• Stomach pain or cramps.

• Enlarged or painful breasts in men or women.

• Irregular menstrual periods.

• Vaginal bleeding in postmenopausal (the end of menstrual cycle) women.

• Difficulty maintaining or achieving an erection.

• Increased hair growth on parts of the body.

• Tiredness.

• Restlessness.

• Deepening of the voice.

Some of the side effects are severe, and the patient should be taken to emergency care if these symptoms occur:

• Hives.

• Itching.

• Difficulty breathing or swallowing.

• Vomiting blood.

• Inability to move arms or legs.

• Changes in a heartbeat.

• Confusion.

• Nausea.

• Extreme tiredness.

• Dry mouth, thirst, dizziness, unsteadiness, headache, or other signs of dehydration.

• Blood in stools.

• Decreased urination.

• Fainting.

• Pain in the upper right part of the stomach.

• Yellowing of the skin or eyes.

When and Why Spironolactone Has to Be Used?

Spironolactone has to be used in combination with other medicines to treat advanced puberty (a condition causing children to develop sexual characteristics too soon and enter puberty before the actual defined age of puberty) in girls who are usually younger than eight years of age and in boys who are usually younger than nine years of age or myasthenia gravis (a disease in which the nerves improperly function and patients can experience weakness; problems with vision, numbness; loss of muscle coordination; and speech, and also bladder control). Spironolactone is used to treat certain female patients with abnormal facial hair. Talk to the doctor about the possible risks of using this medication for the condition.

How Is Spironolactone Manufactured and Supplied?

Spironolactone is available in tablet and suspension forms. Either form has a different medical effect and thus cannot be interchanged.

Tablets:

1. 25 mg: Round, light yellow, film-coated.

2. 50 mg: Oval, light orange, scored, film-coated.

3. 100 mg: Round, peach-colored, scored, film-coated.

Storage and Disposal of Spironolactone:

This medicine has to be stored in a tightly closed container, where children cannot access the medications. It should be stored at room temperature and away from excess heat and moisture, and not in spaces like washrooms. It is important to keep all medication out of reach and away from the glance of children as many containers are not child-resistant, and young children can access them easily. In order to protect young children from poisoning, safety caps should always be locked and immediately placed in a safe location. Medications that are not needed should be disposed of in special ways by making sure that pets, children, and other people cannot consume them. Nevertheless, one should not flush this medication down the toilet. Instead, the best way to dispose of the medication is through a medicine take-back program. Talk to the pharmacist or local garbage or recycling department should be contacted to learn about take-back programs in the community.

Overdose

Acute overdose may cause mental confusion, drowsiness, erythematous or maculopapular rash, nausea, dizziness, or diarrhea. Consuming the medication should be stopped immediately after the symptoms are seen. Vomiting should be induced in the case of overdose, and the stomach should be emptied by lavage. There is no specific antidote to it. Medical help should be taken in such cases.

Missed Dose:

The missed dose should be taken as soon as one remembers it. However, if it is almost time for the next dose, then skip the missed dose and continue the regular dosing schedule. Avoid taking a double dose for a missed one.

Other General Information About Spironolactone:

The doctor will order certain lab tests to check the body's response to Spironolactone. Before having any laboratory tests, tell the doctor and the laboratory personnel that the person is taking Spironolactone. Do not let anyone else take the medicine. The pharmacist should be asked any questions the person has about refilling the prescription. It is important for the patient to keep a list of all of the prescription and nonprescription medicines the patient is taking, as well as any vitamins, minerals, or other dietary supplements. One should bring this list with them each time they visit a doctor or if admitted to a hospital. It is also important to carry with it information in case of emergencies.

For Doctors:

Pharmacology:

1. Mechanism of Action:

Spironolactone and the active metabolites it has are specific pharmacologic antagonists of aldosterone, acting especially via the competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site into the distal convoluted renal tubule. Spironolactone causes raised amounts of sodium and water to be excreted, while potassium is usually retained. Spironolactone acts both as an antihypertensive drug and as a diuretic by this mechanism. It can be administered alone or in association with other diuretic agents that have a more proximal impact on the renal tubule.

2. Pharmacodynamics:

Aldosterone Antagonist Activity:

High levels of the mineralocorticoid aldosterone are present in primary and secondary hyperaldosteronism. Edematous states where secondary aldosteronism is generally involved include hepatic cirrhosis, congestive heart failure, and nephrotic syndrome. Spironolactone counteracts secondary aldosteronism-induced associated sodium loss and the volume depletion caused by active diuretic therapy.

3. Pharmacokinetics:

• Absorption: The mean time to reach the acme of plasma concentration of Spironolactone and the active metabolite, Canrenone, in healthy volunteers is three and four hours, respectively. Food increased the bioavailability of Spironolactone (as measured by AUC) by approximately 96 percent. Patients should establish a routine pattern for taking Spironolactone with meals. Spironolactone and its metabolites are more than 89 percent bound to plasma proteins.

• Elimination: The mean half-life of Spironolactone is two hours. The mean half-life values of its metabolites, including canrenone, 7-alpha-(thiomethyl) Spironolactone (TMS), and 6-beta-hydroxy-7-alpha-(thiomethyl) Spironolactone (HTMS) are 17, 14, and 15 hours, respectively.

• Metabolism: Spironolactone is quickly and extensively metabolized. Metabolites can be divided into two main categories: one in which sulfur of the parent molecule is excreted (for example- canrenone) and one in which the sulfur is retained (for example:- TMS and HTMS). In humans, the potencies of TMS and 7-alpha-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were around a third relative to Spironolactone. Nevertheless, since the serum concentrations of these steroids were undetermined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their lower in vivo activities.

• Excretion: The metabolites are removed primarily through the urine and secondarily in bile.

Warning and Precautions Before Prescribing:

• Hyperkalemia: Spironolactone can induce hyperkalemia. This risk is increased by potassium-containing salt substitutes, impaired renal function or concomitant potassium supplementation, or drugs that increase potassium, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. If hyperkalemia is seen, lower the dose or stop Spironolactone and treat hyperkalemia.

• Worsening Renal Function and Hypotension: Excessive diuresis can induce symptomatic dehydration, worsening renal function, and potassium-containing salt substitutes, particularly in salt-depleted patients or those who are under the treatment of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. Worsening of kidney function may also appear with concomitant use of nephrotoxic drugs. Volume status and renal function should be monitored periodically.

• Metabolic and Electrolyte Abnormalities: In addition to causing hyperkalemia, Spironolactone can cause hyponatremia, hypocalcemia, hypomagnesemia, hypochloremic alkalosis, and hyperglycemia. Rarely gout is precipitated, and asymptomatic hyperuricemia can occur. Serum electrolytes, uric acid, and blood glucose have to be monitored periodically.

• Gynecomastia: Spironolactone can cause gynecomastia. In the Randomized Aldactone Evaluation Study (RALES), patients with heart failure were treated with a mean dose of 26 mg of Spironolactone once daily; about 9 percent of the male subjects developed gynecomastia. The gynecomastia risk increases in a dose-dependent manner with an onset that varies widely from one to two months to over a year. Gynecomastia is generally reversible.

Indications and Uses:

• Heart Failure: The indication for Spironolactone is for the treatment of NYHA (New York Heart Association) Class III to IV heart failure and reduced ejection fraction to increase survival, reduce the need for hospitalization for heart failure, and manage the failure of the heart. Spironolactone is generally administered in association with other heart failure therapies.

• Hypertension: Spironolactone is stated as an additional therapy for the treatment of hypertension to decrease blood pressure in patients who are not sufficiently managed by other agents. Lowering blood pressure reduces the risk of nonfatal and cardiovascular events, fatal myocardial infarctions, and primarily strokes. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes.

• Edema Related to Hepatic Cirrhosis or Nephrotic Syndrome: Spironolactone is suggested for the management of edema in the following settings:

1. Liver cirrhosis is a condition when edema is unresponsive to fluid and sodium restriction.

2. Nephrotic syndrome is a condition when treatment and management of the underlying disease, sodium intake, restriction of fluids, and the use of other diuretics initiate an inadequate response.

Because it raises serum potassium, Spironolactone may be useful for treating edema when the administration of other diuretics has caused hypokalemia.

• Primary Hyperaldosteronism:

1. Pre-operative short-term treatment of patients with primary hyperaldosteronism.

2. Maintenance of long-term therapy for patients with hidden aldosterone-producing adrenal adenomas who are not suitable for surgery.

3. Maintenance of long-term therapy for patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism).

Dosage and Administration:

• General Considerations: Spironolactone can be taken on an empty stomach or with food but has to be taken consistently with respect to food.

• Essential Hypertension Treatment: The recommended initial regular dose is 25 to 100 mg of Spironolactone given in either single or divided doses. The dosage could be titrated at two-week intervals. Doses higher than 100 mg/day particularly do not show additional reductions in blood pressure.

• Heart Failure Treatment: In patients with serum potassium, treatment starts at 25 mg once daily. Patients who tolerate 25 mg once daily can have their dosage increased to 50 mg once daily as clinically indicated. Patients who get hyperkalemia on 25 mg once daily can have the dosage lowered to 25 mg every other day. Initiating therapy should be considered at 25 mg every other day because of the risk of hyperkalemia.

• Edema Treatment: In patients suffering from cirrhosis, therapy should be initiated in a hospital setting and titrated slowly. The suggested initial daily dosage is 100 mg of Spironolactone administered in either single or divided doses but may range from 25 to 200 mg daily. When given as the only agent for diuresis, it should be administered for at least five days prior to increasing the dose to acquire the desired effect.

• Treatment of Primary Hyperaldosteronism: Spironolactone has to be administered in doses of 100 to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, Spironolactone can be administered as long-term maintenance therapy at the lowered effective dosage determined for the individual patient.

Contraindications:

Spironolactone Is Contraindicated in Patients With:

• Concomitant use of Eplerenone.

• Addison’s disease (an uncommon illness that occurs when the body does not make enough of certain hormones).

• Hyperkalemia (a serum or plasma potassium level above the upper limits of normal).

Clinical Trials:

• Heart Failure: The Randomized Aldactone Evaluation Study (RALES) included the placebo-controlled, double-blind study of the effect of Spironolactone on mortality in patients with higher levels of symptomatic heart failure and lower ejection fraction. To be eligible to participate, patients had to have an ejection fraction equal to or less than 33 percent, NYHA class III to IV symptoms, and a history of NYHA class IV symptoms in the last six months before enrollment. Patients with a baseline serum creatinine greater than 2.5 mg/dL or a recent increase of 25 percent or with a baseline serum potassium greater than 5.0 mEq/L were exempted.Follow-up visits and laboratory measurements (including serum potassium and creatinine) were performed every four weeks for the first ten weeks, then every three months for the first year, and then every six months after that. The initial dose of Spironolactone was 25 mg once daily. Patients who were intolerant of the initial dosage regimen had their dose reduced to one 25 mg tablet every other day for one to three weeks. Patients tolerating one tablet daily at eight weeks may have had their dose increased to 50 mg daily at the investigator's discretion. The mean daily dose at the end of the study for patients randomized to Spironolactone was 26 mg.

• Hypertension: The dose-response of Spironolactone for hypertension has not been well characterized. In patients with hypertension, a reduction in systolic blood pressure has been observed at doses ranging from 25 to 100 mg/day. Doses greater than 100 mg/day generally do not show additional reductions in blood pressure.

Drug Interactions:

• Supplements and Drug Supplements Increasing Serum Potassium: Concomitant giving of Spironolactone with potassium supplementation or drugs that can raise potassium can lead to severe hyperkalemia. Potassium supplementation should be stopped in heart failure patients who start Spironolactone.

• Lithium: Like other diuretics, Spironolactone lowers the renal clearance of lithium, thus increasing the risk of lithium toxicity. Lithium levels should be monitored periodically when Spironolactone is administered along with it.

• Non-steroidal Anti-inflammatory Drugs (NSAIDs): In some patients, the ingestion of NSAIDs can lower the diuretic, natriuretic, and antihypertensive effects of diuretics. Hence, when Spironolactone and NSAIDs are used concomitantly, the patient should be monitored closely to determine if the desired effect of the diuretic is acquired.

• Cholestyramine: Hyperkalemic metabolic acidosis was reported in patients administered Spironolactone concurrently with cholestyramine.

• Acetylsalicylic Acid: Acetylsalicylic acid can lower the efficacy of Spironolactone. Hence, when Acetylsalicylic acid and Spironolactone are used concomitantly, Spironolactone can need to be titrated to an increased maintenance dose, and the patient has to be monitored closely to determine if the desired effect is acquired.

Other Specifications:

• In Pregnancy: As there is a potential risk to the male fetus due to the anti-androgenic properties of Spironolactone and animal data, Spironolactone should be avoided in pregnant women or pregnant women of the potential risk to male fetus.

• In Lactating Mothers: Spironolactone is absent in breast milk; however, limited data from a lactating woman at 18 days postpartum reports the presence of the metabolite active in human breast milk in low amounts that are supposed to be clinically inconsequential.

• Geriatric Use: Spironolactone is substantially eliminated by the kidney, and the risk of adverse reactions to this drug can be greater in patients with impaired renal function. Because elderly patients are more likely to have reduced renal function, renal function should be monitored.

• Pediatric Use: Safety and effectiveness in pediatric patients have not been documented or researched enough.