Spironolactonum

General characteristics. Structure:

Active ingredient: 25 mg, 50 mg or 100 mg of Spironolactonum in 1 tablet.

The drug having diuretic, kaliysberegayushchy and anti-hypertensive effect.

Pharmacological properties:

Pharmacodynamics. Competes with Aldosteronum for places of binding on cytoplasmatic mineralokortikoidny receptors. Inhibits Aldosteronum - adjustable exchange of ions of sodium for potassium ions in collective tubules and distal tubules. Brakes a reabsorption of ions of sodium through an apical membrane of cells of a renal epithelium, raises excretion with urine of ions of sodium, chlorine and water, lowers secretion and removal of potassium (kaliysberegayushchy effect), magnesium, urea and increases their concentration in blood. Lowers titrable acidity of urine. Has moderate long-term diuretic effect and weak anti-hypertensive action. The diuretic effect after reception of repeated doses is shown for the 2-5th day and remains within 2–3 days after the reception termination. Spironolactonum as diuretic is most effective at the hypostases connected with the raised products of Aldosteronum, especially when kaliysberegayushchy diuretic action is desirable, including at congestive heart failure, cirrhosis and a nephrotic syndrome. Kaliysberegayushchy action allows to use it at the hypopotassemia caused by other diuretics and also at hypersensitivity to drugs of the foxglove caused by a hypopotassemia.

Anti-hypertensive activity is caused by increase in excretion of ions of sodium and reduction of OTsK and extracellular liquid. Spironolactonum is most effective for the decrease increased the GARDEN and DAD at patients with primary hyper aldosteronism, in most cases essential hypertensia (even in spite of the fact that the level of secretion of Aldosteronum at benign essential hypertensia can be within norm). Hypotensive action is shown on the 2-3rd week of treatment.

Carcinogenicity, mutagenicity, influence on fertility. In researches of chronic toxicity at rats oncogenous action of Spironolactonum, especially concerning endocrine organs and a liver is established. In one research at males of the rats receiving Spironolactonum in the doses, in 25, 75 and 250 times exceeding a daily dose for the person (2 mg/kg) statistically significant dozozavisimy increase in frequency of benign adenomas of a thyroid gland and testicles was revealed. At females of rats statistically significant increase in frequency of malignant tumors of a mammary gland when using average doses was noted. At males of rats dozozavisimy increase in frequency of proliferative changes in a liver was revealed. At the highest level of doses (500 mg/kg) the revealed effects included a gepatotsitomegaliya, the centers of a hyperplasia and a gepatokletochny carcinoma (development of the last was not statistically significant at p=0,05). Cases of development of miyelotsitarny leukemia were observed by Dozozavisimye (at doses over 20 mg/kg/days) at the rats receiving with a forage daily during 1 year of potassium канреноат. In long (biennial) researches of carcinogenicity of potassium of a kanrenoat at rats at peroral introduction miyelotsitarny leukemia and tumors of a liver, a thyroid gland, a small egg and a mammary gland were observed. Potassium канреноат did not cause mutagen effects in tests with use of bacteria or yeast. It caused mutagen effect in some in vitro tests on cells of mammals after metabolic activation, but was not mutagen in vivo. The main metabolites of potassium of a kanrenoat are канренон and kanrenoyevy acid. Spironolactonum is also metabolized to a kanrenon. Increase in frequency of leukemia was not noted at a research of chronic toxicity at rats when using doses of Spironolactonum up to 500 mg/kg/days.

Pharmacokinetics. At intake it is well soaked up from a GIT (bioavailability more than 90%), absorption increases at a concomitant use with food (bioavailability of nearly 100%). It biotransformirutsya quickly and extensively in a liver with formation of several sulfur-containing metabolites, including 7 - alpha thiomethylspirolactonum (TMS), 6-бета-гидроксè7-альфа-тиометилспиролактона (GTMS) and the main active metabolite — a kanrenon.

Antimineralokortikoidny activity of metabolites of Spironolactonum was estimated at adrenalectomized rats and made for a kanrenon, TMS and GTMS 1,10; 1,28 and 0,32 activities of Spironolactonum respectively; affinity of metabolites in relation to aldosteronovy receptors in kidneys of rats made 0,19; 0,86 and 0,06 that of Spironolactonum respectively. The person has an ability of TMC and 7 - alpha thiospirolactonum to recover the electrolytic composition of urine changed under the influence of a synthetic mineralokortikoid — a fludrokortizon, made 0,33 and 0,26 in comparison with Spironolactonum respectively.

Linkng of Spironolactonum and kanrenon with proteins of a blood plasma — more than 90%. Spironolactonum and its metabolites pass through a placental barrier, канренон gets into breast milk. At daily reception of 100 mg within 15 days at 12 healthy volunteers of Cmax  of Spironolactonum it was reached in 2,6 h after the next morning reception and made 80 ng/ml, Cmax  of a kanrenon (181 ng/ml) was registered later 4,3 h, TMS (391 ng/ml) — in 3,2 h, GTMS (125 ng/ml) — in 5,1 h. 10% — in not changed look, and also in the form of metabolites with bile/excrements are removed mainly with urine in the form of metabolites.  Spironolactonum T1/2 — 10 min., T1/2  of a kanrenon sostavlyaet13-24 h (on average 19 h) at reception 1–2 times a day, 9–16 h (on average 12,5 h) at reception 4 times a day.

It was reported about a possibility of use of Spironolactonum independently or as an additional tool at treatment of a hirsutism at women with a syndrome of a polycystosis of ovaries, at a premenstrual syndrome, at family premature puberty at young men, at a bronchopulmonary dysplasia at children; for treatment of acne rash (acne vulgaris) and simplification of manifestations of a mountain disease.

Indications to use:

Edematous syndrome at chronic heart failure, cirrhosis (especially at simultaneous existence of a hypopotassemia and hyper aldosteronism), a nephrotic syndrome; essential hypertensia at adults; ascites; diagnosis and treatment of primary hyper aldosteronism (Conn's syndrome); prevention of a hypopotassemia at treatment by saluretics and at the patients receiving cardiac glycosides, a myasthenia (supportive application).

Route of administration and doses:

Inside. The mode of dosing is set individually. Usual doses for adults: 25-200 mg/days in one or several receptions; if necessary the dose is increased to 400 mg/days. To children usually appoint at the rate of 3 mg/kg/days, once илив 2 receptions, the dose is selected individually.

Features of use:

Use at pregnancy and feeding by a breast. Use of Spironolactonum is contraindicated in the I trimester of pregnancy. In II and the III trimester of pregnancy it is possible only according to strict indications if the expected effect of therapy exceeds potential risk for a fruit. Category of action on a fruit on FDA — C. For the period of treatment it is necessary to stop breastfeeding (канренон — the active metabolite of Spironolactonum — gets into breast milk).

With care appoint at surgical intervention against the background of local and general anesthetics, to elderly patients (the risk of development of a hyperpotassemia is increased). It is not necessary to appoint Spironolactonum together with the HP causing a gynecomastia. At doses over 100 mg/days develop endocrine/anti-androgenic effects more often, action on TsNS and irritation of a mucous membrane of a GIT is shown. During therapy it is necessary to control carefully the content of electrolytes, level of ureal nitrogen, urea and creatinine in blood (especially at elderly patients with a renal failure and/or a liver), regularly to watch the ABP indicators. At development of a hyperpotassemia it is necessary to stop reception of Spironolactonum. It is necessary to avoid receipt in an organism of excess amounts of potassium, including to exclude or limit the food rich with potassium (potatoes, apricots, raisin, tomato juice, etc.), and also HP containing potassium. At treatment by Spironolactonum it is necessary to avoid the use of alcoholic drinks. In an initiation of treatment Spironolactonum drivers of vehicles and people whose profession is connected with the increased concentration of attention should not apply it in operating time. At test for tolerance to glucose at patients with a diabetic nephropathy Spironolactonum should be cancelled, at least, in 3 days prior to test (in connection with risk of a heavy hyperpotassemia).

Side effects:

From a nervous system and sense bodys: dizziness, drowsiness, lethargy, slackness, headache, ataxy, confusion of consciousness.

From bodies of a GIT: nausea, vomiting, diarrhea, spasms, intestinal colic, gastritis, ulcerations and bleedings in a GIT, an abnormal liver function.

From urinogenital system: a gynecomastia (usually reversible, in rare instances can remain after cancellation of HP), mammary gland pain, disturbance of an erection at men, decrease in a potentiality at men, disturbance of a menstrual cycle or an amenorrhea, a metrorrhagia in a climacteric, a hirsutism, change of a voice at women.

From integuments: makulopapulyarny or erythematic skin rashes, alopecia, hypertrichosis, itch, urticaria.

Others: spasms of gastrocnemius muscles, high-quality new growths of a mammary gland, a stethalgia, a leukopenia (including an agranulocytosis), thrombocytopenia, disturbance of electrolytic balance, a hyperpotassemia, increase in blood of ureal nitrogen, creatinine, osteomalacy, medicinal fever.

It was reported about cases of a breast cancer at the men and women receiving Spironolactonum, however relationship of cause and effect is not established.

Interaction with other medicines:

Simultaneous use with indometacin, APF inhibitors, drugs of potassium leads to development of a hyperpotassemia.

In order to avoid a hyperpotassemia do not accept Spironolactonum along with amiloride or Triamterenum.

At a concomitant use with karbenoksolony the therapeutic effect of Spironolactonum since карбеноксолон causes a sodium delay in an organism decreases.

Spironolactonum reduces sensitivity of vessels to noradrenaline that needs to be considered when carrying out the general and local anesthesia at the patients receiving Spironolactonum.

Acetylsalicylic acid weakens diuretic effect of Spironolactonum.

Spironolactonum exponentiates action diuretic and antihypertensives (at simultaneous use with antihypertensives the dose of the last should be reduced by 50%), reduces effect of anticoagulants of indirect action (coumarin derivatives).

Raises T1/2, plasma levels and toxicity of digoxin (at their joint reception it is necessary to reduce a dose or to increase an interval between digoxin receptions).

Spironolactonum combination with triptoreliny, busereliny, gonadoreliny strengthens their action.

Contraindications:

Hypersensitivity, Addison's disease, the acute or quickly progressing renal failure, a chronic renal failure with considerable decrease in secretory function (creatinine Cl less than 10 ml/min.), an anury, a hyperpotassemia, a hyponatremia, a hypercalcemia.

Restrictions to use. Decrease in secretory function of kidneys, an abnormal liver function (hypersensitivity to changes of electrolytic balance), a diabetes mellitus (especially diabetic nephropathy), predisposition to a metabolic acidosis (at acidosis the giperkaliyemichesky effect of Spironolactonum amplifies, Spironolactonum can promote development of acidosis), disturbances of a menstrual cycle and/or increase in chest glands, AV blockade (strengthening in connection with development of a hyperpotassemia is possible).

Overdose:

Symptoms: nausea, vomiting, drowsiness, dizziness, confusion of consciousness, spasm of gastrocnemius muscles, skin rash, diarrhea; organism dehydration, disturbance of water and electrolytic balance is possible.

Treatment: termination of administration of drug, induction of vomiting, gastric lavage, symptomatic therapy of dehydration and disturbances of water and electrolytic balance, arterial hypotension, maintenance of the vital functions; in case of a hyperpotassemia — 20–50% of solution of glucose, bystry in/in introduction, and insulin — 0,25–0,5 PIECES/g of glucose. Kaliyvyvodyashchy diuretics and ion-exchange resins are used. Carrying out a hemodialysis is possible. There is no specific antidote.

Storage conditions:

To store at a temperature of 15-25 °C, in dry, protected from light and the place, unavailable to children. Period of validity 3 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets of 25 mg, 50 mg and 100 mg. 20 tablets in each blister, on one, two or three blisters together with the application instruction in cardboard packaging.