Spironolactone
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Spironolactone
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| Systematic (IUPAC) name | |
| 7α-Acetylthio-3-oxo-17α-pregn-4-ene-21,17-carbolactone | |
| Identifiers | |
| CAS number | |
| ATC code | C03 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C24H32O4S |
| Mol. mass | 416.574 g/mol |
| SMILES | & |
| Synonyms | Aldactone Spirotone Spirolactone |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | Hepatic |
| Half life | 10 minutes |
| Excretion | Urine, bile |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status | |
| Routes | Oral |
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.
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[edit] Mechanism of action
Spironolactone inhibits the effect of aldosterone by competing for intracellular aldosterone receptor 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.[1]
[edit] 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.
[edit] 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).[2] 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 significantly less symptoms of CHF and were hospitalized less frequently.
The mechanism of this effect is also mediated by inhibiting aldosterone, which in heart failure leads to myocardial fibrosis, sodium retention, and vascular dysfunction.
[edit] 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.[3] Since it also affects steroid receptors elsewhere in the body, 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.[4]
There are indications that taking this drug can reduce the odds for developing Alzheimer's. "We observed the greatest reduction in AD risk specifically with potassium-sparing diuretics. It is not clear why potassium-sparing diuretics in particular should be associated with a reduced risk of AD, but it is well known that both loop and thiazide diuretics reduce plasma potassium concentration while potassium-sparing diuretics (including triamterene, spironolactone, and amiloride hydrochloride) typically lead to increased concentrations. As yet unpublished findings from the Gothenberg Study also suggest that increased potassium levels may be associated with a reduced risk of dementia.34 Consistent with this idea are observations that low potassium concentrations are associated with oxidative stress,35-36 inflammation,35-36 platelet aggregation,37 and vasoconstriction,38 all of which are possible contributors to AD pathogenesis." See: http://archneur.ama-assn.org/cgi/content/full/63.5.noc60013v1
People using this drug should avoid salt substitutes containing potassium.[5]
However, a more serious issue may be the drug's interference with antidepressant effectiveness. The drug is actually (among its other receptor interactions) a mineralocorticoid (MR) antagonist, and has been found to worsen antidepressant outcome in the treatment of major depression, presumably by interfering with normalization of the HPA axis in patients receiving antidepressant therapy. Given that there are many patients on this drug who are also depressed and receiving classical first-line antidepressant drugs particularly SSRIs, this becomes a poorly appreciated but potentially major issue. (See Holsboer, F. The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J. Psychiatr. Res. 33, 181–214 (1999) for details).
[edit] 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.[6] In light of this research, Sandoz has recommended that unnecessary use of spironolactone be avoided.
[edit] See also
[edit] References
- ^ Berardesca, E; Gabba P, Ucci G, Borroni G, Rabbiosi G. (1988). "Topical spironolactone inhibits dihydrotestosterone receptors in human sebaceous glands: an autoradiographic study in subjects with acne vulgaris.". Int J Tissue React. 10 (2): 115-119. PMID 2972662.
- ^ Pitt B, Zannad F, Remme W, Cody R, Castaigne A, Perez A, Palensky J, Wittes J (1999). "The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.". N Engl J Med 341 (10): 709-17. doi:. PMID 10471456.
- ^ Verhamme KMC, Mosis G, Dieleman JP, et al. (2006). "Spironolactone and risk of upper gastrointestinal events: population based case-control study". Brit Med J 333 (7563): 330–3. doi:.
- ^ Wandelt-Freerksen E. (1977). "Aldactone in the treatment of sarcoidosis of the lungs". JZ Erkr Atmungsorgane. 149(1): 156-9. PMID 607621.
- ^ Advisory Statement (pdf). Klinge Chemicals / LoSalt. Retrieved on 2007-03-15.
- ^ Spironolactone RX Monograph (html). Sandoz Inc.. Retrieved on 2007-05-02.
[edit] External links
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