Spironolactone

Spironolactone is used to treat heart failure , edema such as nephrotic syndrome or ascites in people with liver disease, hypertension , low levels of potassium in the blood , secondary hyperaldosteronism , and Conn's syndrome . Spironolactone is most commonly used to treat heart failure ^[11] . Spironolactone itself is a weak diuretic, because it is primarily aimed at the distal nephron (collecting tube), where only a small amount of sodium is reabsorbed, but it can be combined with other diuretics to increase effectiveness. The classification of spironolactone as a is considered obsolete ^[12] .

Spironolactone has antiandrogenic activity. For this reason, it is often used to treat various dermatological conditions in which androgens play a role. Some of these uses include acne , seborrhea , hirsutism, and hair loss in women ^[13] . Spironolactone is the most commonly used drug for the treatment of hirsutism in the United States ^[14] . High doses of spironolactone, which are necessary for significant antiandrogenic effects, are not recommended for men because of the high risk of feminization and other side effects. In addition, spironolactone is also widely used to treat symptoms of hyperandrogenism , such as polycystic ovary syndrome , in women ^[15] . The medicine is not approved by the Food and Drug Administration for use as antiandrogens; for such purposes it is used off-label ^[16] .

Heart Failure

Although loop diuretics remain the first line for most people with heart failure, spironolactone has shown a decrease in both morbidity and mortality in numerous studies and remains an important treatment for fluid retention, edema, and symptoms of heart failure. Currently, the American Heart Association recommends the use of spironolactone in patients with NYHA class II — IV heart failure, in whom the left ventricular ejection rate is less than 35% ^[17] .

In a randomized research study that examined people with severe congestive heart failure, it was found that in people treated with spironolactone, the relative risk of death is 0.70 or a 30% reduction in overall risk compared with the placebo group, which indicates significant health and mortality benefits when using this medication. People who participated in the study also had fewer symptoms of heart failure and were less likely to be hospitalized ^[18] . Similarly, it has shown its benefit and is recommended for patients who have recently suffered a heart attack and have an ejection fraction of less than 40%, and who develop symptoms consistent with heart failure, or who have a history of diabetes . Spironolactone should be considered a good additional agent, especially in those patients who are “not yet” optimized for ACE inhibitors and beta-blockers ^[17] . It should be noted that a recent 2014 randomized double-blind study of spironolactone in patients with symptomatic heart failure with a “saved" ejection fraction (ie> 45%) did not reveal a decrease in mortality from cardiovascular events, sudden cardiac arrest, and did not reveal a decrease in hospitalization when comparing spironolactone with placebo ^[19] .

Transgender hormone therapy

Spironolactone is often used as a component of feminizing hormone therapy in transgender women, mainly in the United States, where cyproterone acetate is not available. Used in conjunction with estrogen ^{[20] [21] [22]} . Other clinical effects include reduced male hair growth on the body, development of mammary glands, feminization in general, and the absence of spontaneous erections ^[22] .

Spironolactone is usually used in small doses from 25 to 50 mg / day for heart failure ^{[23] [24] [25] [26]} , in the treatment of primary hypertension - from 25 to 200 mg / day ^{[23] [26]} , and for hyperaldosteronism and ascites due to cirrhosis - in large doses from 100 to 400 mg / day ^{[27] [28] [29] [30]} . The medicine is usually used in large doses from 100 to 200 mg / day in the treatment of skin and hair diseases in women ^{[31] [32] [33] [34] [35]} , and in large doses from 100 to 400 mg / day for feminizing hormone replacement therapy for transgender women ^{[36] [37] [38]} .

In the distal nephron, spironolactone prevents the aldosterone retention of sodium and water and inhibits the potassium-excreting effect of aldosterone , reduces the synthesis of permeases in the aldosterone-dependent portion of the collecting tubules and distal tubules. By binding to aldosterone receptors , it increases the excretion of sodium, chlorine and water ions in the urine, reduces the excretion of potassium and urea ions, and reduces the acidity of urine.

Increased diuresis causes a hypotensive effect, which is variable.

The maximum effect is observed 7 hours after taking the capsules inside and lasts at least 24 hours.

The diuretic effect is manifested on 2-5 days of treatment.

Suction

After ingestion, it is rapidly and completely absorbed from the digestive tract ; bioavailability is 100%. After daily intake of 100 mg of spironolactone for 15 days, Cmax is 80 ng / ml, the time to reach Cmax after the next morning dose is 2-6 hours.

Distribution

It binds to plasma proteins by 98%.

Spironolactone penetrates poorly into organs and tissues, while spironolactone and its metabolites penetrate the placental barrier, and canrenone - into breast milk . Vd - 0.05 l / kg.

Metabolism

In the process of biotransformation, active sulfur-containing metabolites of 7-alpha-thiomethylspironolactone and canrenone are formed in the liver . Canrenone reaches its Cmax after 2-4 hours, its connection with blood plasma proteins is 90%.

Withdrawal

T1 / 2 - 13-24 hours. It is excreted mainly with urine (50% - in the form of metabolites, 10% - unchanged) and partially with feces . Excretion of canrenone (mainly with urine) is two-phase, T1 / 2 in the first phase - 2-3 hours, in the second - 12-96 hours.

Pharmacokinetics in special clinical cases

With cirrhosis of the liver and heart failure, the duration of T1 / 2 increases without signs of cumulation, the probability of which is higher in chronic renal failure and hyperkalemia.

• essential hypertension (as part of combination therapy);
• edema syndrome in chronic heart failure (can be used as monotherapy and in combination with standard therapy);
• conditions in which secondary hyperaldosteronism can be detected, including cirrhosis of the liver, accompanied by ascites and / or edema, nephrotic syndrome and other conditions accompanied by edema;
• hypokalemia / hypomagnesemia (as an aid to its prevention during treatment with diuretics and when it is impossible to use other methods of correction of potassium levels);
• primary hyperaldosteronism (Conn's syndrome) - for a short preoperative course of treatment;
• to establish a diagnosis of primary hyperaldosteronism.

With essential hypertension, the daily dose for adults is usually 50-100 mg once and can be increased to 200 mg, and the dose should be increased gradually, once every 2 weeks. To achieve an adequate response to therapy, the drug must be taken for at least 2 weeks. If necessary, carry out dose adjustment.

With idiopathic hyperaldosteronism, the drug is prescribed in a dose of 100-400 mg / day.

With severe hyperaldosteronism and hypokalemia, the daily dose is 300 mg (maximum 400 mg) for 2-3 doses, with improvement, the dose is gradually reduced to 25 mg / day.

With hypokalemia and / or hypomagnesemia caused by diuretic therapy, Veroshpiron is prescribed at a dose of 25-100 mg / day, once or in several doses. The maximum daily dose is 400 mg if oral potassium preparations or other methods of replenishing its deficiency are ineffective.

In the diagnosis and treatment of primary hyperaldosteronism as a diagnostic tool with a short diagnostic test, Veroshpiron is prescribed for 4 days at 400 mg / day, distributing the daily dose in several doses per day. With an increase in the concentration of potassium in the blood while taking the drug and a decrease after withdrawal, it can be assumed that primary hyperaldosteronism is present. With a long diagnostic test, the drug is prescribed in the same dose for 3-4 weeks. When correcting hypokalemia and arterial hypertension, primary hyperaldosteronism can be assumed.

After the diagnosis of hyperaldosteronism is established using more accurate diagnostic methods, Veroshpiron should be taken in a daily dose of 100-400 mg as a short course of preoperative treatment of primary hyperaldosteronism, dividing it into 1-4 doses throughout the entire period of preparation for a surgical operation. If the operation is not indicated, then Veroshpiron is used for long-term maintenance therapy, while the lowest effective dose is used, which is selected individually for each patient.

In the treatment of edema against the background of nephrotic syndrome, the daily dose for adults is usually 100-200 mg. No effect of spironolactone on the main pathological process was detected, and therefore the use of this drug is recommended only in cases where other types of therapy are ineffective.

In case of edematous syndrome against the background of chronic heart failure, the drug is prescribed daily, for 5 days, at 100-200 mg / day in 2-3 doses, in combination with a “loop” or thiazide diuretic. Depending on the effect, the daily dose is reduced to 25 mg. The maintenance dose is selected individually. The maximum daily dose is 200 mg.

For edema with cirrhosis of the liver, the daily dose of Veroshpiron for adults is usually 100 mg if the ratio of sodium and potassium ions (Na + / K +) in urine exceeds 1.0. If the ratio is less than 1.0, then the daily dose is usually 200-400 mg. The maintenance dose is selected individually.

With edema in children, the initial dose is 1-3.3 mg / kg body weight or 30-90 mg / m² / day in 1-4 doses. After 5 days, a dose adjustment is carried out and, if necessary, it is increased by 3 times compared to the original.

From the digestive system: nausea, vomiting, diarrhea, ulceration and bleeding from the gastrointestinal tract, gastritis, intestinal colic, abdominal pain, constipation, impaired liver function.

From the side of the central nervous system and peripheral nervous system: ataxia, lethargy, dizziness, headache, drowsiness, lethargy, confusion, muscle spasm, calf muscle cramps.

On the part of the hematopoietic system: agranulocytosis, thrombocytopenia, megaloblastosis.

From the side of metabolism: hyperuricemia, hypercreatininemia, increased urea concentration, hyperkalemia, hyponatremia, metabolic hyperchloremic acidosis or alkalosis.

From the endocrine system: coarsening of the voice, in men - gynecomastia (the probability of development depends on the dose, duration of treatment and is usually reversible), decreased potency and erection; in women - menstrual irregularities, dysmenorrhea, amenorrhea, menorrhagia in the menopause, hirsutism , pain in the mammary gland, breast carcinoma (no connection with the drug has been established).

Allergic reactions: urticaria, rarely - maculopapular and erythematous rash, drug fever, pruritus.

Dermatological reactions: alopecia, hypertrichosis.

From the urinary system: acute renal failure.

• Addison's disease;
• hyperkalemia
• hyponatremia;
• severe renal failure (CC less than 10 ml / min);
• anuria
• pregnancy;
• lactation period;
• hypersensitivity to any of the components of the drug.

With caution, the drug should be prescribed for hypercalcemia, metabolic acidosis, AV blockade (hyperkalemia enhances it), diabetes mellitus (with confirmed or suspected chronic renal failure), diabetic nephropathy, surgical interventions, taking medications that cause gynecomastia, local and general anesthesia, menstrual irregularities, enlarged mammary glands, liver failure, cirrhosis, as well as elderly patients.

The use of spironolactone is contraindicated in pregnancy and lactation.

When using spironolactone, a temporary increase in the level of urea nitrogen in the blood serum is possible, especially with reduced renal function and hyperkalemia. It is also possible the development of hyperchloremic metabolic acidosis. When prescribing Veroshpiron to patients with impaired renal and hepatic function, elderly patients require regular monitoring of serum electrolytes and renal function.

Taking spironolactone makes it difficult to determine the concentration of digoxin, cortisol and adrenaline in the blood.

Despite the absence of a direct effect on carbohydrate metabolism, the presence of diabetes mellitus, especially with diabetic nephropathy, requires special care when prescribing spironolactone because of the possibility of developing hyperkalemia.

При лечении НПВС на фоне приёма спиронолактона следует контролировать функцию почек и уровень электролитов крови.

Во время лечения спиронолактоном употребление алкоголя противопоказано, следует избегать употребления пищи, богатой калием.

В начальном периоде лечения запрещается управлять автомобилем и заниматься видами деятельности, требующими повышенной концентрации внимания и быстроты психомоторных реакций. Длительность ограничений устанавливается в индивидуальном порядке.

Симптомы: тошнота, рвота, головокружение, диарея, кожная сыпь, гиперкалиемия (парестезии, мышечная слабость, аритмии), гипонатриемия (сухость во рту, жажда, сонливость), гиперкальциемия, дегидратация, увеличение концентрации мочевины.

Лечение: промывание желудка, симптоматическое лечение дегидратации и артериальной гипотензии. При гиперкалиемии необходимо нормализовать водно-электролитный обмен с помощью калийвыводящих диуретиков, быстрого парентерального введения раствора декстрозы (5-20 % растворы) с инсулином из расчёта 0.25-0.5 ЕД на 1 г декстрозы; при необходимости возможно повторное введение декстрозы. В тяжёлых случаях проводят гемодиализ.

Спиронолактон при одновременном применении снижает эффект антикоагулянтов ( гепарина , производных кумарина, индандиона) и митотана; усиливает действие диуретиков и антигипертензивных препаратов, усиливает эффект трипторелина, бусерелина, гонадорелина.

При приёме спиронолактона одновременно с препаратами калия , калиевыми добавками и калийсберегающими диуретиками, ингибиторами АПФ, антагонистами ангиотензина II возрастает риск развития гиперкалиемии.

На фоне применения спиронолактона уменьшается токсичность сердечных гликозидов (так как нормализация уровня калия в крови препятствует развитию токсичности).

Спиронолактон снижает чувствительность сосудов к норэпинефрину (требует соблюдения осторожности при проведении анестезии).

Петлевые и тиазидные диуретики усиливают и ускоряют диуретический и натрийуретический эффекты спиронолактона.

ГКС также усиливают диуретический и натрийуретический эффект спиронолактона при гипоальбуминемии и/или гипонатриемии.

Салицилаты, индометацин снижают диуретический эффект спиронолактона.

Хлорид аммония, колестирамин при одновременном применении с спиронолактоном способствуют развитию гиперкалиемического метаболического ацидоза, а флудрокортизон вызывает парадоксальное усиление канальцевой секреции калия.

При одновременном применении Верошпирон усиливает токсическое действие лития из-за снижения его клиренса.

Veroshpiron with simultaneous use enhances the metabolism of phenazone (antipyrine), increases the half-life of digoxin (digoxin intoxication is possible), accelerates the metabolism and excretion of carbenoxolone . Carbenoxolone promotes sodium retention with spironolactone.

As a result of additional studies conducted by virologists at the University of Utah , the activity of the drug in cell culture was detected that was directed against the human herpes virus type 4 ^{[39] [40]} .