indication

Used primarily to treat low-renin hypertension, hypokalemia, and Conn's syndrome.

pharmacology

Spironolactone is a synthetic 17-lactone steroid which is a renal competitive aldosterone antagonist in a class of pharmaceuticals called potassium-sparing diuretics. On its own, spironolactone is only a weak diuretic, but it can be combined with other diuretics. Due to its anti-androgen effect, it can also be used to treat hirsutism, and is a common component in hormone therapy for male-to-female transgendered people. Spironolactone inhibits the effect of aldosterone by competing for intracellular aldosterone receptor in the distal tubule cells. This increases the secretion of water and sodium, while decreasing the excretion of potassium. Spironolactone has a fairly slow onset of action, taking several days to develop and similarly the effect diminishes slowly.

mechanism of action

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 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 which act more proximally in the renal tubule. Aldosterone interacts with a cytoplasmic mineralocorticoid receptor to enhance the expression of the Na+, K+-ATPase and the Na+ channel involved in a Na+ K+ transport in the distal tubule . Spironolactone bind to this mineralcorticoid receptor, blocking the actions of aldosterone on gene expression. Aldosterone is a hormone; its primary function is to retain sodium and excrete potassium in the kidneys.

toxicity

The oral LD₅₀ of spironolactone is greater than 1,000 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. Spironolactone has been shown to be a tumorigen in chronic toxicity studies in rats.

biotransformation

Rapidly and extensively metabolized. The metabolic pathway of spironolactone is complex and can be divided into two main routes: those in which the sulfur moiety is retained and those in which the sulfur moiety is removed by dethioacetylation. Spironolactone is transformed to a reactive metabolite that can inactivate adrenal and testicular cytochrome P450 enzymes. It also has anti-androgenic activity.

absorption

Fairly rapidly absorbed from the gastrointestinal tract. Food increases the bioavailability of unmetabolized spironolactone by almost 100%.

half life

10 minutes

route of elimination

The metabolites are excreted primarily in the urine and secondarily in bile.

drug interactions

Benazepril: Increased risk of hyperkalemia

Candesartan: Increased risk of hyperkalemia

Captopril: Increased risk of hyperkalemia

Cholestyramine: Increased risk of acidosis and hyperkalemia

Cilazapril: Increased risk of hyperkalemia

Digoxin: Increased digoxin levels and decreased effect in presence of spironolactone

Enalapril: Increased risk of hyperkalemia

Eplerenone: This association presents an increased risk of hyperkalemia

Eprosartan: Increased risk of hyperkalemia

Fosinopril: Increased risk of hyperkalemia

Irbesartan: Increased risk of hyperkalemia

Lisinopril: Increased risk of hyperkalemia

Losartan: Increased risk of hyperkalemia

Mitotane: Spironolactone antagonizes the effect of mitotane

Perindopril: Increased risk of hyperkalemia

Polystyrene sulfonate: Risk of alkalosis in renal impairment

Potassium: Increased risk of hyperkalemia

Quinapril: Increased risk of hyperkalemia

Ramipril: Increased risk of hyperkalemia

Telmisartan: Telmisartan may increase the hyperkalemic effect of Spironolactone. Monitor for increased serum potassium concentrations during concomitant therapy.

Tobramycin: Increased risk of nephrotoxicity

Trandolapril: Increased risk of hyperkalemia. Monitor serum potassium levels.

Treprostinil: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.