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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. IUPAC Nomenclature is a system of naming Chemical compounds and of describing the science of Chemistry in general CAS registry numbers are unique numerical identifiers for Chemical compounds Polymers biological sequences mixtures and Alloys They are also referred to The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs It is controlled by the WHO Collaborating Centre for Drug A section of the Anatomical Therapeutic Chemical Classification System. PubChem is a Database of chemical Molecules The system is maintained by the National Center for Biotechnology Information (NCBI a component The DrugBank database available at the University of Alberta is a unique Bioinformatics and Cheminformatics resource that combines detailed drug (i A chemical formula is a way of expressing information about the Atoms that constitute a particular Chemical compound, and how the relationship between those atoms changes Carbon (kɑɹbən is a Chemical element with the symbol C and its Atomic number is 6 Hydrogen (ˈhaɪdrədʒən is the Chemical element with Atomic number 1 Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the Sulfur or sulphur (ˈsʌlfɚ see spelling below) is the Chemical element that has the Atomic number 16 The molecular mass (abbreviated m of a substance, more commonly referred to as molecular weight and abbreviated as MW, is the Mass of one 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. This article deals with the general meaning of the term "synonym" In Pharmacology, bioavailability is used to describe the fraction of an administered Dose of unchanged drug that reaches the Systemic circulation, one of Drug metabolism is the Metabolism of drugs, their Biochemical modification or degradation usually through specialized enzymatic systems The liver is a vital organ in the human body and is present in Vertebrates and some other animals The biological half-life of a substance is the time it takes for a substance (drug radioactive nuclide or other to lose half of its pharmacologic physiologic or radiologic activity Excretion is the process of eliminating waste products of Metabolism and other non-useful materials Urine is a liquid waste product of the body secreted by the Kidneys by a process of filtration from Blood and Excreted through the Urethra. Bile or gall is a bitter yellow or green Alkaline fluid secreted by Hepatocytes from the Liver of most Vertebrates In many species The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical if it is used as directed by the mother during For a topic outline on this subject see List of basic Australia topics. The United States of America —commonly referred to as the The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom, the UK or Britain,is a Sovereign state located In Pharmacology and Toxicology, a route A diuretic is any Drug that elevates the rate of urination ( Diuresis) An antiandrogen, or androgen antagonist, is any of a group of Hormone Receptor antagonist compounds that are capable of preventing or inhibiting the biologic
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. lactone is a cyclic Ester in Organic chemistry. It is the condensation product of an Alcohol group and a Carboxylic acid Aldosterone is a hormone that causes the tubules of the kidneys to retain sodium and water Potassium-sparing diuretics are Diuretic drugs that do not promote the secretion of Potassium into the Urine. Heart failure is a Cardiac condition that occurs when a problem with the structure or function of the Heart impairs its ability to supply In Medicine ( Gastroenterology) ascites (also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more Renin (pronounced "Ree-nin" or "Rē-nin" (ˈriːnɨn also known as Angiotensinogenase, is a circulating Enzyme that participates in the body's Hypertension, also referred to as high blood pressure, HTN or HPN, is a medical condition in which the Blood pressure is chronically elevated Hypokalemia refers to the condition in which the concentration of Potassium in the blood is low Primary Aldosteronism, also known as primary Hyperaldosteronism and Conn syndrome, is characterized by the overproduction of the Mineralocorticoid 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. Androgen is the generic term for any natural or synthetic compound usually a Steroid Hormone, that stimulates or controls the development and maintenance of masculine Hirsutism (from Latin hirsutus = shaggy hairy is defined as excessive and increased Hair growth in women in locations where the occurrence of Terminal A transwoman (also spelled trans woman or trans-woman) is a male-to-female transsexual and the term transwoman is preferred by many such Transgender (trænzˈdʒɛndɚ from ( Latin) derivatives 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. Alopecia or hair loss is the medical description of the loss of hair from the head or body sometimes to the extent of Baldness. Acne vulgaris (commonly called acne) is a Skin disease caused by changes in the Pilosebaceous units (skin structures consisting of a Hair follicle In Medicine, a topical Medication is applied to body surfaces such as the Skin or Mucous membranes for example the Vagina Baldness involves the state of lacking hair where it often grows especially on the head
Contents |
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). The mineralocorticoid receptor (or MR MLR MCR also called Aldosterone receptor, is officially labelled Nuclear receptor subfamily 3 group C member The distal convoluted tubule ( DCT) is a portion of Kidney Nephron between the Loop of Henle and the Collecting duct system. This increases the excretion of water and sodium, while decreasing the excretion of potassium. Sodium (ˈsoʊdiəm is an element which has the symbol Na( Latin natrium, from Arabic natrun) atomic number 11 atomic mass 22 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. The androgen receptor ( AR) also known as NR3C4 (nuclear receptor subfamily 3 group C member 4 is a type of Nuclear receptor which is activated by Dihydrotestosterone ( DHT) (Full name 5α-Dihydrotestosterone, abbreviating to 5α-DHT; INN: androstanolone; commonly called [1]
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. Canrenone is an Aldosterone antagonist.The active form and first metabolite of Spironolactone Potassium canrenoate ( INN) or canrenoate potassium ( USAN) the potassium salt of canrenoic acid is an Aldosterone antagonist 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). Death is the termination of the biological functions that define living Organisms It refers both to a specific In Medicine, Epidemiology and Actuarial science, the term morbidity can refer to the state of poor health (from Latin Heart failure is a Cardiac condition that occurs when a problem with the structure or function of the Heart impairs its ability to supply The New York Heart Association (NYHA Functional Classification provides a simple way of classifying the extent of heart failure. [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. In Statistics and mathematical Epidemiology, relative risk (RR is the risk of an event (or of developing a disease relative to exposure 70 or a 30% relative risk reduction. The relative risk reduction is a measure used in Epidemiology. Patients in the study arm also had significantly less symptoms of CHF and were hospitalized less frequently. Heart failure is a Cardiac condition that occurs when a problem with the structure or function of the Heart impairs its ability to supply
The mechanism of this effect is also mediated by inhibiting aldosterone, which in 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. In Human anatomy, the stomach is a J-shaped hollow muscular organ of the Gastrointestinal tract involved in the second phase of Digestion, following In Anatomy of the Digestive system, the duodenum is a hollow jointed tube about 25-30 cm (10-12 in long connecting the Stomach to the Jejunum [3] Since it also affects steroid receptors elsewhere in the body, it can cause gynecomastia, menstrual irregularities and testicular atrophy. Gynecomastia, or gynaecomastia, ˌgaɪnəkoʊˈmæstiə is the development of abnormally large Mammary glands in Males resulting in breast enlargement which Other side effects include ataxia, erectile dysfunction, drowsiness and rashes. Ataxia (from Greek α- as a negative prefix + -τάξις, meaning "lack of order" is a neurological sign and symptom consisting A carcinogenic effect has been demonstrated in rats. The term carcinogen refers to any substance Radionuclide or radiation that is an agent directly involved in the promotion of Cancer or in the fatation of its propagation Spironolactone has been shown to be immunosuppressive in the treatment of sarcoidosis. Sarcoidosis, also called sarcoid (from the Greek sarx, meaning "flesh" or Besnier-Boeck disease, is an immune system disorder characterized [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).
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. Potassium canrenoate ( INN) or canrenoate potassium ( USAN) the potassium salt of canrenoic acid is an Aldosterone antagonist Canrenone is an Aldosterone antagonist.The active form and first metabolite of Spironolactone 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.
See also
References
- ^ Berardesca, E; Gabba P, Ucci G, Borroni G, Rabbiosi G. More than half of men are affected by Male pattern baldness by age 50 and baldness treatments are estimated to be a US $1 billion per year industry (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:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. 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:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.
- ^ 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. Year 2007 ( MMVII) was a Common year starting on Monday of the Gregorian calendar in the 21st century. Events 44 BC - Julius Caesar, Dictator of the Roman Republic, is stabbed to death by Marcus Junius Brutus,
- ^ Spironolactone RX Monograph (html). Sandoz Inc. . Retrieved on 2007-05-02. Year 2007 ( MMVII) was a Common year starting on Monday of the Gregorian calendar in the 21st century. Events 1194 - King Richard I of England gives Portsmouth its first Royal Charter.
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