Spironolactone

Spironolactone (marketed under the trade names Aldactone, Novo-Spiroton, Spiractin, Spirotone, Verospiron or Berlactone) is a diuretic and is used as an antiandrogen.

It is a synthetic 17-lactone drug which is a renal competitive aldosterone antagonist in a class of pharmaceuticals called potassium-sparing diuretics, used primarily to treat heart failure, ascites in patients with liver disease, low-renin hypertension, hypokalemia, and Conn's syndrome as well as high blood pressure. On its own, spironolactone is only a weak diuretic, but it can be combined with other diuretics. About one person in one hundred with hypertension has elevated levels of aldosterone; in these persons the antihypertensive effect of spironolactone may exceed that of complex combined regimens of other antihypertensives. 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 transsexual and transgendered people. It is also used for treating hair loss and acne in women and can be used as a topical medication for treatment of male baldness.

Mechanism of action
Spironolactone inhibits the effect of aldosterone by competing for intracellular aldosterone receptors in the distal tubule cells (it actually works on aldosterone receptors in the collecting duct). This increases the excretion 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. Spironolactone has anti-androgen activity by binding to the androgen receptor and preventing it interacting with dihydrotestosterone.

Pharmacokinetics
Spironolactone is fairly rapidly absorbed from the gastrointestinal tract. It is also rapidly metabolised and bound in plasma proteins. Many of its metabolites are also active and one of them, canrenone as potassium canrenoate, is used parenterally when rapid effect is needed. Spironolactone's half-life is 85 minutes, but canrenone's half-life is 10 to 35 hours, depending on the dose. The main elimination route is in the urine and some also in the bile.

Mortality and morbidity benefit in severe heart failure
Spironolactone was shown to have a significant mortality and morbidity benefit in the Randomized Aldactone Evaluation Study (RALES), which studied people with severe congestive heart failure (New York Heart Association functional class III or IV). Patients in the study arm of the trial (those receiving spironolactone) had a relative risk of death (when compared to the placebo group) equal to 0.70 or a 30% relative risk reduction. Patients in the study arm also had fewer symptoms of CHF and were hospitalized less frequently.

The mechanism of this effect is also mediated by inhibiting aldosterone, which in conjunction with heart failure leads to myocardial fibrosis, sodium retention, and vascular dysfunction.

Adverse effects and interactions
Spironolactone is associated with an increased risk of bleeding from the stomach and duodenum, but a causal relationship between the two has not been established. Because it also affects androgen receptors and other steroid receptors, it can cause gynecomastia, menstrual irregularities and testicular atrophy. Other side effects include ataxia, erectile dysfunction, drowsiness and rashes. A carcinogenic effect has been demonstrated in rats. Spironolactone has been shown to be immunosuppressive in the treatment of sarcoidosis.

Spironolactone often increases serum potassium levels and can cause hyperkalemia, a potentially serious condition. Therefore, it is recommended that people using this drug avoid potassium supplements and salt substitutes containing potassium. Doctors usually recommend periodic screening of serum potassium levels and some patients may be advised to limit dietary consumption of potassium.

Research has also shown that spironolactone can interfere with the effectiveness of antidepressant treatment. The drug is actually (among its other receptor interactions) a mineralocorticoid (MR) antagonist, and has been found to reduce the effectiveness of antidepressant drugs in the treatment of major depression, presumably by interfering with normalization of the hypothalamic-pituitary-adrenal axis in patients receiving antidepressant therapy.

Carcinogenicity
Studies of spironolactone and the related compound potassium canrenoate (which, like spironolactone, metabolizes to canrenone) in rats for one to two year periods show an increase in carcinogenesis in the thyroid gland, testes, liver, breasts, and myelocytic leukocytes. Mammalian cells, depending on the presence of metabolic activation, show mixed results for mutagenicity in vitro. In light of this research, Sandoz has recommended that unnecessary use of spironolactone be avoided.

Other potential benefits
It has been suggested that spironolactone can reduce the risk of Alzheimer's disease. In one study, researchers observed a reduction in the risk of Alzheimer's specifically associated with potassium-sparing diuretics. Unpublished findings from other studies, including the Gothenberg Study have suggested that higher potassium levels may be associated with a lower risk of dementia.

It is widely reported that most American diets contain more sodium than is necessary and lack the optimal daily intake of potassium. Therefore, spironolactone could theoretically counter the effects of the typical American diet as it tends to promote sodium excretion and potassium retention. However, there is no proof that it is beneficial for persons whose serum potassium and sodium levels are within the normal range. Few if any doctors would recommend using spironolactone in the absence of conditions for which it is normally indicated.