Spironolactone

MECHANISM OF ACTION

Spironolactone works by antagonizing aldosterone at mineralocorticoid receptors in the distal renal tubules and collecting ducts. By blocking aldosterone, it reduces sodium and water reabsorption while conserving potassium, leading to a diuretic effect without causing significant potassium loss. Additionally, spironolactone has anti-androgenic activity, which can influence hormone-related conditions such as hirsutism or acne.

PHARMACOKINETICS

Absorption

Spironolactone is well absorbed orally, primarily in the gastrointestinal tract. Its absorption rate and bioavailability are significantly affected by the presence of food. 

Distribution

Spironolactone has a volume of distribution of approximately 0.7 L/kg in adults, indicating moderate distribution into body tissues. Its active metabolites, such as canrenone, contribute to its prolonged pharmacological effects.

Metabolism

Spironolactone is extensively metabolized in the liver to several active metabolites, including canrenone, 7α-thiomethylspironolactone, and 7α-thiospironolactone. These metabolites contribute significantly to its potassium-sparing diuretic and aldosterone-antagonist effects, and their formation accounts for spironolactone’s prolonged duration of action despite the relatively short half-life of the parent compound.

Excretion

Spironolactone and its active metabolites are primarily excreted via the urine (approximately 47%) and to a lesser extent via the feces (about 37%). Its metabolites, especially canrenone, account for much of the drug’s prolonged pharmacological activity.

PHARMACODYNAMICS

Spironolactone’s pharmacodynamics are based on its role as a competitive antagonist of aldosterone at mineralocorticoid receptors in the distal renal tubules and collecting ducts. By blocking aldosterone, it inhibits sodium and water reabsorption while conserving potassium and hydrogen ions, producing a potassium-sparing diuretic effect. Additionally, spironolactone exhibits anti-androgenic activity by antagonizing androgen receptors and inhibiting androgen synthesis, which can affect conditions like hirsutism, acne, and certain hormone-sensitive disorders.

DOSAGE AND ADMINISTRATION

Adults:

• For edema: Typically 25–200 mg per day, either as a single dose or divided into 1–2 doses.

• For hypertension: Usually 25–100 mg per day, often given once daily or in divided doses.

• For primary hyperaldosteronism: 100–400 mg per day, adjusted based on response.

• For heart failure: Standard dose is 12.5–25 mg once daily, titrated according to clinical response and potassium levels.

Pediatric Use:

• Doses are weight-based, often 1–3 mg/kg per day in divided doses, depending on the condition being treated.

Administration:

• Administer orally, with or without food.

• Take consistently at the same time each day to maintain stable blood levels.

• Monitor potassium levels regularly, especially in patients with renal impairment or those on other potassium-altering drugs.

DRUG INTERACTIONS

Spironolactone interacts with many drugs, including NSAIDs (like ibuprofen and naproxen), other blood pressure medications (like ACE inhibitors and ARBs), digoxin, lithium, potassium supplements, and certain muscle relaxants. These interactions can increase the risk of hyperkalemia (high potassium levels), reduce the effectiveness of the medications, or lead to other serious side effects. Combining spironolactone with certain drugs, such as venlafaxine, can also increase the risk of dangerously low sodium levels (hyponatremia).

FOOD INTERACTIONS

Spironolactone’s effectiveness and safety can be influenced by certain dietary factors. High-potassium foods such as bananas, oranges, tomatoes, potatoes, and spinach should be limited, as spironolactone already conserves potassium, and excessive intake can lead to hyperkalemia. Salt substitutes, which often contain potassium, should also be avoided for the same reason. Additionally, licorice can reduce the diuretic effect of spironolactone and may increase blood pressure, while excessive alcohol consumption may raise the risk of dizziness or low blood pressure. Patients are generally advised to maintain a balanced diet and consult their healthcare provider before making significant dietary changes while taking spironolactone.

CONTRAINDICATIONS

Spironolactone is contraindicated in patients with hyperkalemia, severe renal impairment or anuria, and addison’s disease. It should not be used in individuals with known hypersensitivity to spironolactone or other steroidal diuretics. Caution is also advised during pregnancy and breastfeeding, as the drug can affect fetal development and may pass into breast milk. Additionally, concurrent use with potassium-sparing diuretics or potassium supplements is contraindicated due to the risk of dangerously high potassium levels.

SIDE EFFECTS

• Dizziness/lightheadedness and drowsiness

• Headache

• Gastrointestinal issues: Nausea, vomiting, diarrhea, and stomach cramps

• Increased urination

• Breast changes: Tenderness, pain, or enlargement in both men and women (gynecomastia in men)

• Changes in sex drive or performance

• Fatigue or unusual tiredness

• Muscle cramps (especially in the legs) 

• Irregular menstrual cycles, spotting, or missed periods 

OVERDOSE

• Drowsiness and confusion

• Nausea, vomiting, and diarrhea

• Dizziness or lightheadedness (due to low blood pressure or dehydration)

Signs of high potassium levels (hyperkalemia):

• Muscle weakness or unusual tiredness

• Tingling or a “pins and needles” sensation in the hands, feet, or lips.

• Slow or irregular heartbeat, heart palpitations, or chest pain

• Shortness of breath

Signs of dehydration or low sodium levels (hyponatremia):

• Extreme thirst and dry mouth

• Decreased urination

• Severe weakness or fatigue

• Skin rash 

TOXICITY

Spironolactone toxicity mainly arises from electrolyte disturbances, especially hyperkalemia, and fluid imbalances. While an acute overdose may produce milder symptoms, toxicity can become life-threatening, particularly in patients with pre-existing kidney or liver disease or those taking other medications that influence potassium levels.