Spironolactone

Spironolactone is an antihypertensive agent belonging to Potassium Sparing Diuretics.

Spironolactone is a potassium-sparing diuretic which is used for the treatment of hypertension, hyperaldosteronism, edema due to various conditions, hirsutism (off-label) and hypokalemia.

The peak plasma concentration (Cmax) of Spironolactone is reached 0.5 to 1.5 hours after dosing in healthy volunteers; for the active metabolite canrenone, the Cmax is reached around 2.5 to 5 hours after dosing. Spironolactone and its metabolites are more than 90% bound to plasma proteins. Spironolactone is rapidly and extensively metabolized primarily by CYP 3A4/5, and to a lesser extent by CYP2C8. In humans, the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were approximately a third relative to Spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities. The metabolites are excreted primarily in the urine and secondarily in bile.

Spironolactone shows common side effects Vomiting, diarrhoea, stomach pain or cramps, enlarged or painful breasts in men or women, irregular menstrual periods, vaginal bleeding in post-menopausal ('after the change of life', the end of monthly menstrual periods) women, difficulty maintaining or achieving an erection, deepening of voice, increased hair growth on parts of the body, drowsiness, tiredness, restlessness, etc.

Spironolactone is available in the form of Oral Tablet and Oral Suspension.

Spironolactone is available in India, US, UK, Japan, Austria, Canada, Philippines, China and Japan.

Spironolactone belonging to the Potassium Sparing Diuretics acts as an antihypertensive agent.

Spironolactone competitively inhibits aldosterone dependent 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.

The onset of action of Spironolactone is found to be 2-4 hours.

The Duration of Action for Spironolactone in the body is about 2-3 days.

The Tmax was found within 0.5-1.5 hours (by oral tablet) and 2.5-5 hours (by oral suspension).

Spironolactone is available in the form of Oral Tablet and Oral Suspension.

Spironolactone Tablets or Suspension are taken orally, and it is usually taken once a day.

Spironolactone is a potassium-sparing diuretic which is used for the treatment of hypertension, hyperaldosteronism, edema due to various conditions, hirsutism (off-label) and hypokalemia. Spironolactone may be used alone or with other medications.

Spironolactone is an antihypertensive agent belonging to Potassium Sparing Diuretics. It competes with aldosterone for receptor sites in the distal renal tubules, increasing sodium chloride and water excretion while conserving potassium and hydrogen ions; may block the effect of aldosterone on arteriolar smooth muscle as well.

Spironolactone is approved for use in the following clinical indications

• Heart Failure

Spironolactone is indicated for treatment of heart failure and reduced ejection fraction to increase survival, manage edema, and reduce the need for hospitalization for heart failure. Spironolactone is usually administered in conjunction with other heart failure therapies.

• Hypertension

Spironolactone is indicated as add-on therapy for the treatment of hypertension, to lower blood pressure in patients who are not adequately controlled on other agents. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes.

• Edema Associated with Hepatic Cirrhosis or Nephrotic Syndrome

Spironolactone is indicated for the management of edema in the following settings:

• Cirrhosis of the liver when edema is not responsive to fluid and sodium restriction.

• Nephrotic syndrome when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics produce an inadequate response. Because it increases serum potassium, Spironolactone may be useful for treating edema when administration of other diuretics has caused hypokalemia.

• Primary Hyperaldosteronism

• Short-term preoperative treatment of patients with primary hyperaldosteronism.

• Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are not candidates for surgery.

• Long-term maintenance therapy for patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism).

• Heart Failure

Heart failure with reduced ejection fraction:

Tablet: Oral: Initial: 12.5 to 25 mg once daily.

May double the dose every 4 weeks if serum potassium remains <5 mEq/L and renal function is stable, up to a maximum target dose of 50 mg/day in 1 to 2 divided doses.

Suspension: Oral: Initial: 10 to 20 mg once daily.

Consider a starting dose of 10 mg once daily in patients at increased risk of hyperkalemia. May titrate to 37.5 mg once daily if serum potassium remains <5 mEq/L and renal function is stable.

• Hypertension

Tablet: Oral: Initial: 25 mg once daily; titrate as needed after ~2 to 4 weeks based on response and tolerability up to 100 mg once daily.

Patients with severe asymptomatic hypertension and no signs of acute end organ damage should be evaluated for medication titration within 1 week.

Suspension: Oral: Initial: 20 mg/day in 1 or 2 divided doses; titrate as needed after ~2 to 4 weeks based on response and tolerability up to 75 mg/day in 1 or 2 divided doses. Patients with severe asymptomatic hypertension and no signs of acute end organ damage should be evaluated for medication titration within 1 week.

• Edema Associated with Hepatic Cirrhosis or Nephrotic Syndrome

Tablet: Oral: Initial: 100 mg once daily; titrate every 3 to 5 days based on response and tolerability; usual maximum dose: 400 mg once daily.

For small-volume ascites in patients who weigh ≤50 kg, some experts recommend a starting dose of 50 mg once daily.

• Primary Hyperaldosteronism:

Tablet: Oral: Initial: 12.5 to 25 mg once daily gradually titrate to the lowest effective dose; usual maximum dose: 400 mg/day.

For surgical candidates, the last dose should be administered the day of surgery; discontinue Spironolactone on postoperative day 1.

Although not approved, there have been certain off-label indications. These include

• Heart failure with preserved ejection fraction (off-label use):

Tablet: Oral: Initial: 12.5 mg once daily; may double the dose every 2 to 4 weeks if serum potassium and renal function are stable, up to a maximum target dose of 50 mg/day in 1 or 2 divided doses.

• Post-myocardial infarction, complicated by reduced ejection fraction (off-label use):

Tablet: Oral: Initial: 12.5 to 25 mg once daily; may double the dose every 4 weeks if serum potassium remains <5 mEq/L and renal function is stable, up to a maximum target dose of 50 mg/day in 1 to 2 divided doses.

Suspension: Oral: Initial: 10 to 20 mg once daily. Consider a starting dose of 10 mg once daily in patients at increased risk of hyperkalemia. May titrate to 37.5 mg once daily if serum potassium remains <5 mEq/L and renal function is stable.

• Hirsutism, females (alternative agent) (off-label use):

Tablet: Oral: Initial: 50 mg twice daily; may increase to 100 mg twice daily as needed. Assess response at 6-month intervals before adjusting dose, adding additional agents, or switching to alternative therapy.

• Acne vulgaris, females, moderate to severe (alternative agent) (off-label use):

Tablet: Oral: Initial: 25 to 50 mg/day in 1 to 2 divided doses; titrate as needed based on response and tolerability to a usual effective dose of 50 to 100 mg/day in 1 to 2 divided doses; maximum dose: 200 mg/day.

• Hormone therapy for transgender females, male-to-female (adjunctive agent) (off-label use):

Tablet: Oral: Initial: 25 mg once or twice daily in combination with other appropriate agents. Increase at 1-week intervals based on response and tolerability to a usual dose of 100 to 300 mg/day in 2 divided doses; maximum dose: 400 mg/day. Adjust dose with a goal of suppressing serum testosterone levels into the normal range for females (<50 ng/dL).

Spironolactone is available in various strengths 25mg, 50mg, 100mg and 5mg/ml.

Spironolactone is available in the form of Oral Tablet and Oral Suspension.

Avoid potassium-containing salt substitutes such as Bananas, oranges, potatoes, peas, mushrooms, cantaloupe, honeydew, apricots, grapefruit, raisins, and dates, while you are taking Spironolactone.

Spironolactone is contraindicated in patients with

• Hyperkalemia
• Addison’s disease
• Concomitant use of eplerenone

• Hyperkalemia

Spironolactone can cause hyperkalemia. This risk is increased by impaired renal function or concomitant potassium supplementation, potassium-containing salt substitutes or drugs that increase potassium, such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Closer monitoring may be needed when Spironolactone is given with other drugs that cause hyperkalemia or in patients with impaired renal function. If hyperkalemia occurs, decrease the dose or discontinue Spironolactone and treat hyperkalemia.

• Hypotension And Worsening Renal Function

Excessive diuresis may cause symptomatic dehydration, hypotension and worsening renal function, particularly in salt-depleted patients or those taking angiotensinconverting enzyme inhibitors and angiotensin II receptor blockers. Worsening of renal function can also occur with concomitant use of nephrotoxic drugs (e.g., aminoglycosides, cisplatin, and NSAIDs). Monitor volume status and renal function periodically.

• Electrolyte And Metabolic Abnormalities

In addition to causing hyperkalemia, Spironolactone can cause hyponatremia, hypomagnesemia, hypocalcemia, hypochloremia alkalosis, and hyperglycemia. Asymptomatic hyperuricemia can occur and rarely gout is precipitated. Monitor serum electrolytes, uric acid and blood glucose periodically.

• Gynecomastia

Spironolactone can cause gynecomastia. In RALES, patients with heart failure treated with a mean dose of 26 mg of Spironolactone once daily, about 9% of the male subjects developed gynecomastia. The risk of gynecomastia increases in a dose-dependent manner with an onset that varies widely from 1-2 months to over a year. Gynecomastia is usually reversible.

Consumption of alcohol during treatment with Spironolactone may cause lightheadedness, fainting, dizziness.

Canrenone, a major (and active) metabolite of Spironolactone, appears in human breast milk. Because Spironolactone has been found to be tumorigenic in rats, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. If use of the drug is deemed essential, an alternative method of infant feeding should be instituted.

Pregnancy category C

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Avoid potassium-containing salt substitutes such as Bananas, oranges, potatoes, peas, mushrooms, cantaloupe, honeydew, apricots, grapefruit, raisins, and dates, while you are taking Spironolactone.

• Common Adverse effects

Vasculitis, Chloasma, erythematous maculopapular rash, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, Amenorrhea, decreased libido, hyperglycemia, hypocalcemia, hypomagnesemia, hyponatremia, hypovolemia, Abdominal cramps, diarrhea, gastritis, gastrointestinal hemorrhage, gastrointestinal ulcer, nausea, vomiting, Erectile dysfunction, irregular menses, mastalgia, postmenopausal bleeding, Agranulocytosis (Whitling 1997), leukopenia, thrombocytopenia, Hepatotoxicity, Anaphylaxis, Drug reaction with eosinophilia and systemic symptoms, Ataxia, confusion, dizziness, drowsiness, headache, lethargy, nipple pain, Lower limb cramp, Renal failure syndrome, renal insufficiency.

• Rare Adverse effects

Gout, hyperkalemia, hyperuricemia, metabolic acidosis (in patients with cirrhosis), ovarian cyst (in a premature neonate).

• Lithium

Like other diuretics, Spironolactone reduces the renal clearance of lithium, thus increasing the risk of lithium toxicity. Monitor lithium levels periodically when Spironolactone is coadministered.

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effect of loop, potassium-sparing, and thiazide diuretics. Therefore, when Spironolactone and NSAIDs are used concomitantly, monitor closely to determine if the desired effect of the diuretic is obtained.

• Digoxin

Spironolactone and its metabolites increase the apparent exposure to digoxin. In patients taking concomitant digoxin, measure serum digoxin concentrations before initiating Spironolactone using an assay that does not interact with Spironolactone. Reduce digoxin concentrations by decreasing the dose by approximately 15-30%or by modifying the dosing frequency and continue monitoring.

• Cholestyramine

Hyperkalemic metabolic acidosis has been reported in patients given Spironolactone concurrently with cholestyramine.

• Acetylsalicylic Acid

Acetylsalicylic acid may reduce the efficacy of Spironolactone. Therefore, when Spironolactone and acetylsalicylic acid are used concomitantly, Spironolactone may needto be titrated to higher maintenance dose and the patient should be observed closely to determine if the desired effect is obtained.

• CYP2C8 And CYP3A Substrates

Spironolactone is an irreversible inhibitor for CYP2C8 and CYP3A4/5 in vitro. Therefore, Spironolactone may increase the exposure of other co-administered drugs that are metabolized by CYP2C8 and CYP3A4/5. Dosage adjustments of the drugs metabolized by CYP2C8 (e.g., repaglinide) and CYP3A4/5 (e.g., midazolam, sirolimus and tacrolimus) may be necessary if they are given concurrently with Spironolactone.

The common side effects of Spironolactone include the following

• Common

Vomiting, diarrhoea, stomach pain or cramps, enlarged or painful breasts in men or women, irregular menstrual periods, vaginal bleeding in post-menopausal ('after the change of life', the end of monthly menstrual periods) women, difficulty maintaining or achieving an erection, deepening of voice, increased hair growth on parts of the body, drowsiness, tiredness, restlessness.

• Rare
  

Muscle weakness, pain, or cramps pain, burning, numbness, or tingling in the hands or feet, inability to move arms or legs, changes in heartbeat, confusion, nausea, extreme tiredness, dry mouth, thirst, dizziness, unsteadiness, headache, or other signs of dehydration, unusual bleeding or bruising, lack of energy, loss of appetite, pain in the upper right part of the stomach, yellowing of the skin or eyes, flu-like symptoms, rash, hives, itching, difficulty breathing or swallowing, vomiting blood, blood in stools, decreased urination, fainting.

• Pregnancy

Pregnancy Category C

Teratology studies with Spironolactone have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose. No teratogenic or other embryotoxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Because of its anti-androgenic activity and the requirement of testosterone for male morphogenesis, Spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day between gestation days 13 and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed. Offspring exposed during late pregnancy to 50 and 100 mg/kg/day doses of Spironolactone exhibited changes in the reproductive tract including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction, that persisted into adulthood. There are no adequate and well-controlled studies with Spironolactone in pregnant women. Spironolactone has known endocrine effects in animals including progestational and antiandrogenic effects. The antiandrogenic effects can result in apparent estrogenic side effects in humans, such as gynecomastia. Therefore, the use of Spironolactone in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the fetus.

• Nursing Mothers

Spironolactone is not present in breastmilk; however, limited data from a lactating woman at 17 days postpartum reports the presence of the active metabolite, canrenone, in human breast milk in low amounts that are expected to be clinically inconsequential. In this case, there were no adverse effects reported for the breastfed infant after short term exposure to Spironolactone; however, long term effects on a breastfed infant are unknown. There are no data on Spironolactone effects on milk production. Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Spironolactone and any potential adverse effects on the breastfed child from Spironolactone or from the underlying maternal condition.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

Spironolactone is substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, monitor renal function.

• The oral LD50 of Spironolactone is greater than 1000 mg/kg in mice, rats, and rabbits.
• Acute overdosage of Spironolactone may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia, or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage. Hyperkalemia may occur, especially in patients with impaired renal function.
• Treatment: Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions. Patients who have renal impairment may develop hyperkalemia. In such cases, discontinue Spironolactone.

Pharmacodynamic

Originally Spironolactone was only studied for its potassium sparing diuretic effect. Spironolactone competitively inhibits mineralocorticoid receptors in the distal convoluted tubule to promote sodium and water excretion and potassium retention. Inhibition of this receptor leads to increased renin and aldosterone levels. Spironolactone is structurally similar to progesterone and as a result is associated with progestogenic and antiandrogenic effects.

Pharmacokinetics

• Absorption

The peak plasma concentration (Cmax) of Spironolactone is reached 0.5 to 1.5 hours after dosing in healthy volunteers; for the active metabolite canrenone, the Cmax is reached around 2.5 to 5 hours after dosing.

• Distribution
  

Spironolactone and its metabolites are more than 90% bound to plasma proteins.

• Metabolism and Excretion
  

Spironolactone is rapidly and extensively metabolized primarily by CYP 3A4/5, and to a lesser extent by CYP2C8. Metabolites can be divided into two main categories: those in which sulfur of the parent molecule is removed (e.g., canrenone) and those in which the sulfur is retained (e.g., TMS and HTMS). In humans, the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were approximately a third relative to Spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities. The metabolites are excreted primarily in the urine and secondarily in bile.

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