SPIROTIL TABLETS

Indications

• Hypertension
• Heart failure
• Edema associated with liver cirrhosis
• Nephrotic syndrome
• Primary hyperaldosteronism
• Hirsutism
• Acne

Dosage

Children: Refer to the BNF for Children for

Adults: For hypertension, the initial dose is 100 mg once daily, adjusted as necessary. For heart failure, the typical dose is 12.5 to 25 mg once daily, with adjustments based on clinical response. Maximum doses can reach 400 mg per day in specific cases.

Mechanism of action

Spironolactone and its active metabolites act as aldosterone antagonists. They competitively bind to mineralocorticoid receptors in the distal convoluted renal tubule, inhibiting sodium reabsorption and promoting potassium retention. This results in diuresis and a decrease in blood pressure. The drug also demonstrates antiandrogenic effects by inhibiting testosterone synthesis and blocking androgen receptors.

Pharmacodynamics

Spironolactone promotes sodium and water excretion and retains potassium, leading to its potassium-sparing diuretic effect. It increases renin and aldosterone levels while exhibiting both progestogenic and anti-androgenic actions. The drug has low affinity for glucocorticoid receptors and also exhibits anti-inflammatory effects.

Pharmacokinetics

Spironolactone is well absorbed following oral administration, with peak plasma concentrations occurring within 1 to 3 hours. It is extensively metabolized in the liver, primarily through CYP450 enzymes, resulting in active metabolites. The elimination half-life ranges from 1.5 to 2 hours, but its effects can last longer due to the pharmacological activity of its metabolites. Spironolactone is excreted mainly in urine, with a small amount eliminated in feces.

Contra-indications

• Hyperkalemia
• Severe renal impairment
• Addison's disease
• Anuria
• Concurrent use of potassium-sparing diuretics

Adverse effects

• Hyperkalemia
• Hyponatremia
• Gastrointestinal disturbances (nausea, vomiting, diarrhea)
• Gynecomastia
• Menstrual irregularities
• Dizziness
• Headache
• Fatigue
• Rash
• Electrolyte imbalances

Interactions

• Potassium supplements and potassium-sparing diuretics (increased risk of hyperkalemia)
• ACE inhibitors (increased risk of hyperkalemia)
• NSAIDs (may reduce the diuretic effect of spironolactone)
• Digoxin (spironolactone may increase digoxin levels)
• Diuretics (may enhance hypotensive effects)

Precautions

• Monitor renal function and electrolytes regularly
• Use cautiously in patients with hepatic impairment
• Caution in patients with a history of electrolyte imbalances
• Avoid abrupt withdrawal in patients receiving long-term therapy

Pregnancy

Spironolactone is classified as pregnancy category C. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Spironolactone is excreted in breast milk. It is advised to exercise caution when administering to nursing mothers.

Storage

Store at room temperature (15-30°C), away from moisture and direct light. Keep out of reach of children.

Formulations

• Oral tablets (25 mg, 50 mg, 100 mg)

Mechanism of action

Aldosterone is a key hormone in the renin-angiotensin-aldosterone system. By binding to the mineralocorticoid receptor at the distal tubules and collecting duct, it causes sodium reabsorption and potassium secretion, increases vascular stiffness and remodelling, and activates pro-inflammatory pathways. Spironolactone and its active metabolites are aldosterone antagonists that produce a potassium-sparing diuretic effect. They competitively bind to 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 is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents that act more proximally in the renal tubule. Spironolactone can exert antiandrogenic effects by several mechanisms: it can destroy testicular CYP and decrease 17alpha-hydroxylase activity, resulting in decreased testosterone synthesis; and it can inhibit 5alpha-dihydrotestosterone binding to cytosolic androgen receptor in the prostate. Spironolactone exhibits antiandrogenic effects in males and females. The mechanism of antiandrogenic activity of spironolactone is complex and appears to involve several effects of the drug. Spironolactone decreases testosterone biosynthesis by inhibiting steroid 17alpha-monooxygenase (17alpha-hydroxylase) activity, possibly secondary to destruction of microsomal cytochrome P-450 in tissues with high steroid 17alpha-monooxygenase activity (e.g., testes, adrenals). The drug also appears to competitively inhibit binding of dihydrotestosterone to its cytoplasmic receptor protein, thus decreasing androgenic actions at target tissues. Spironolactone-induced increases in serum estradiol concentration also may contribute to its antiandrogenic activity, although such increases may not occur consistently; such increases appear to result from increased conversion of testosterone to estradiol. Spironolactone may have variable effects on serum 17-hydroxyprogesterone concentrations, possibly decreasing its production by inhibiting steroid 17alpha-monooxygenase activity or decreasing its conversion (with resultant accumulation) to androstenedione by inhibiting cytochrome P450-dependent 17alpha-hydroxyprogesterone aldolase (17,20-desmolase) activity. Serum progesterone concentrations may increase with the drug secondary to decreased hydroxylation (via steroid 17alpha-monooxygenase) to 17-hydroxyprogesterone. In children, compensatory increases in lutropin (luteinizing hormone, LH) and follicle-stimulating hormone (FSH) secretion can occur, probably secondary to the drug's antiandrogenic effects (i.e., a feedback response to decreasing serum testosterone concentrations and/or peripheral androgenic activity). MEDICATION (VET): Spironolactone is used most frequently and is a competitive antagonist of aldosterone. Aldosterone is elevated in animals with congestive heart failure in which the renin-angiotensin system is activated in response to hyponatremia, hyperkalemia, and reductions in blood pressure or cardiac output. Aldosterone is responsible for increasing sodium and chloride reabsorption and potassium and calcium excretion from renal tubules. Spironolactone competes with aldosterone at its receptor site, causing a mild diuresis and potassium retention. High concentrations of spironolactone have been reported to interfere with steroid biosynthesis by inhibiting 11 beta- and 18-, 21-, and 17 alpha-hydroxylase.

Pharmacodynamics

Spironolactone has a potassium-sparing diuretic effect. It promotes sodium and water excretion and potassium retention. It increases renin and aldosterone levels. Spironolactone is a mineralocorticoid receptor antagonist and has a low affinity for the glucocorticoid receptor. It also exhibits progestogenic and anti-androgenic actions as it binds to the androgen receptor and, to a lesser extent, estrogen and progesterone receptors. Spironolactone exhibits anti-inflammatory effects.