スピロノラクトン

外観

白色～うすい黄褐色, 結晶～粉末

溶解性

エタノール、メタノール及びアセトンに溶け、水にほとんど溶けない。

解説

7α-acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone．C24H32O4S(416.58)．17α-エチニル-5-アンドロステロン-3β,17β-ジオールを原料として，17位を不飽和ラクトンとし，還元後チオ酢酸と加熱して合成する．スピロノラクトンは，微黄色～淡黄褐色の粉末．わずかに特異な臭気があり，味はわずかに苦い．融点134～135 ℃(再固化し201～202 ℃ で分解)．ほとんどの有機溶媒に可溶，水に不溶．[α]_D²⁰"－33.5°(クロロホルム)．λmax 238 nm(ε 20200)．アルドステロンきっ抗利尿薬として用いられる．LD50  ＞ 1000 mg/kg(ラット，経口)． 森北出版「化学辞典（第2版）

用途

特に、アルドステロン分泌が異常亢進する原発性アルドステロン症では第一選択の治療薬である。

用途

スピロノラクトン (spironolactone) はカリウム保持性利尿薬（抗アルドステロン薬）のひとつ。主に心不全、肝硬変性腹水、高血圧治療薬としてフロセミドやクロロチアジドと併用される。

用途

抗アルドステロン剤です。ア ルドステロンに拮抗し、ナトリウム排泄を促 進し、ナトリウム- カリウムイオン交感反応 抑制作用を示します。

用途

アルドステロン拮抗作用物質 です。

用途

利尿剤。副腎(ふくじん)皮質ホルモンのうちの鉱質コルチコイドであるアルドステロンの拮抗(きっこう)物質である。腎の遠位尿細管においてアルドステロンと拮抗し、ナトリウムの排泄(はいせつ)を促進し、カリウムの排泄を阻害して、利尿効果を発揮する。降圧作用も有する。チアジド系降圧利尿薬に比べカリウムの喪失が少ない。心性浮腫(ふしゅ)、腎性浮腫、肝性浮腫などの浮腫や高血圧症の治療に用いられる。微粉末とすることにより効果の増大をみる。1日50～100ミリグラムを経口投与する。［幸保文治］

効能

血圧降下薬, 利尿薬, アルドステロン拮抗薬

商品名

アルダクトン (ファイザー); スピロノラクトン (キョーリンリメディオ)

化学的特性

White to Off White Solid

使用

Spironolactone, an aldosterone-, and competitive androgen-receptor-antagonist and 5-alpharductase- inhibitor, indicated for the treatment of androgen dependent hirsutism, ideally in doses of 50 to 200 mg per day accompanying the intake of oral contraceptives with the same seven day break in between. Side effects concerning the length of the menstrual cycle, the increase of blood pressure or potassium levels may occur. Spironolactone is the number one drug in the treatment of hirsutism in the US (Farquhar et al., 2003). In other countries the prescription of spironolactone for the treatment of hirsutism may be off-label.

適応症

Spironolactone (Aldactone) is a compound originally developed as a mineralocorticoid antagonist and is used as a diuretic and antihypertensive agent. However, at high doses spironolactone binds to the androgen receptor. In clinical practice it is a weak androgen antagonist used to treat hirsutism in women by blocking testosterone binding to androgen receptors in hair follicles. Use of spironolactone in women for the treatment of hirsutism or male pattern baldness can result in elevated serum potassium levels; these levels should be checked within 1 month of starting the medication.

定義

ChEBI: A steroid lactone that is 17alpha-pregn-4-ene-21,17-carbolactone substituted by an oxo group at position 3 and an alpha-acetylsulfanyl group at position 7.

世界保健機関（WHO）

Spironolactone, an aldosterone antagonist, has been widely used for over 25 years in the treatment of hypertension and in the management of refractive oedema. Evidence that long-term administration of high doses are tumorigenic in the rat has recently led to restriction of its use by some national regulatory authorities although the significance of this finding with respect to clinical use is not certain. In 1987 spironolactone was transferred from the main list to the complementary list of the WHO Model List of Essential Drugs. (See also WHO comments for canrenone and potassium canrenoate). (Reference: (WHODI) WHO Drug Information, 2(1), , 1988)

生物学の機能

Spironolactone (Aldactone) is structurally related to aldosterone and acts as a competitive inhibitor to prevent the binding of aldosterone to its specific cellular binding protein. Spironolactone thus blocks the hormone-induced stimulation of protein synthesis necessary for Na⁺ reabsorption and K⁺ secretion. Spironolactone, in the presence of circulating aldosterone, promotes a modest increase in Na⁺ excretion associated with a decrease in K⁺ elimination. The observations that spironolactone is ineffective in adrenalectomized patients and that the actions of spironolactone can be reversed by raising circulating al-dosterone blood levels (surmountable antagonism) support the conclusion that spironolactone acts by competitive inhibition of the binding of aldosterone with receptor sites in the target tissue. Spironolactone acts only when mineralocorticoids are present.

一般的な説明

Spironolactone, 7α-(acetylthio)-17α-hydroxy-3-oxopregn-4-ene-3-one-21-carboxylic acidγ-lactone (Aldactone) is an aldosterone antagonist of greatmedical importance because of its diuretic activity.

危険性

Questionable carcinogen.

生物活性

Competitive mineralocorticoid (aldosterone) receptor antagonist that exhibits antihypertensive activity in vivo . Also displays antiandrogen activity and inhibits steroid hormone biosynthesis.

作用機序

Spironolactone is a potassium sparing diuretic that has a different mechanism of action than other drugs of this class. It is a competitive antagonist of aldosterone, and its action is most effective when the level of circulated aldosterone in the organism is high.

薬理学

Spironolactone (Aldactone) is the only diuretic that has been shown in a double-blind multicenter prospective clinical trial to improve survival in CHF. The addition of spironolactone to digitalis and an angiotensinconverting enzyme (ACE) inhibitor significantly improved survival among patients with chronic severe heart failure.
Spironolactone competitively inhibits the binding of aldosterone to cytosolic mineralocorticoid receptors in the epithelial cells in the late distal tubule and collecting duct of the kidney. Aldosterone enhances salt and water retention at the expense of enhanced renal K and H excretion. Spironolactone enhances diuresis by blocking sodium and water retention while retaining potassium. An obvious potential side effect is hyperkalemia, which is aggravated by the potassium-retaining properties of the ACE inhibitors. The likely concomitant use of the loop diuretic furosemide, which depletes K , dictates careful monitoring of serum potassium to avoid life-threatening rhythm disturbances.
There is also evidence for the existence of mineralocorticoid receptors on cardiac myocytes. This raises the intriguing possibility that spironolactone could mediate important direct effects on the myocardium in CHF.

臨床応用

Spironolactone has been used clinically in the following conditions:
1. Primary hyperaldosteronism. Used as an aid in preparing patients with adrenal cortical tumors for surgery.
2. Hypokalemia. Used in patients with low serum K⁺ resulting from diuretic therapy with other agents. Its use should be restricted to patients who are unable to supplement their dietary K⁺ intake or adequately restrict their salt intake or who cannot tolerate orally available KCl preparations.
3. Hypertension and congestive heart failure. Although spironolactone may be useful in combination with thiazides, the latter remain the drugs of first choice. Fixed-dose combinations of spironolactone and a particular thiazide (e.g., Aldactazide) generally offer no therapeutic advantage over either component given separately and tend to restrict the ability of the clinician to determine the optimal dosage of each drug for a particular patient.
4. Cirrhosis and nephrotic syndrome. Spironolactone is a mild diuretic and may be useful in treating the edema that occurs in these two clinical conditions, that is, when excessive K⁺ loss is to be avoided.

副作用

Serum electrolyte balance should be monitored periodically, since potentially fatal hyperkalemia may occur,especially in patients with impaired renal function or excessive K⁺ intake (including the K⁺ salts of coadministered drugs, e.g., potassium penicillin). Spironolactone can induce hyponatremia and in cirrhotic patients, metabolic acidosis.A variety of gastrointestinal disturbances may accompany spironolactone administration. These include diarrhea, gastritis, gastric bleeding, and peptic ulcers. Spironolactone is contraindicated in patients with peptic ulcers. Spironolactone may also cause elevated blood urea nitrogen, drowsiness, lethargy, ataxia, confusion, and headache. Gynecomastia and menstrual irregularity in males and females, respectively, can occur. Painful gynecomastia (directly related to dosage level and duration of therapy), which is generally reversible, may necessitate termination of therapy. Animal studies demonstrating tumorigenic potential support the clinical judgment that spironolactone alone or in combination should not be used for most patients who require diuretic therapy and its unnecessary use should be avoided.

安全性プロファイル

Poison by intraperitoneal route. Human reproductive effects by ingestion and possibly other routes: men, impotence and breast development; women, menstrual cycle changes or disorders, changes in the breasts and lactation. An experimental teratogen. Other experimental reproductive effects. Other human systemic effects by ingestion: agranulocytosis, kidney tubule damage, increased urine volume, and changes in blood sodium and calcium levels. Questionable carcinogen. When heated to decomposition it emits toxic fumes of SOx,. Used to treat hypertension, edema of congestive heart failure, cirrhosis, and kidney failure. 0

代謝

Spironolactone is poorly absorbed after oral administration and has a delayed onset of action; it may take several days until a peak effect is produced. It has a somewhat slower onset of action than triamterene and amiloride (discussed later), but its natriuretic effect is modestly more pronounced, especially during long-term therapy. Spironolactone is rapidly and extensively metabolized, largely to the active metabolite canrenone. Canrenone and potassium canrenoate, its K⁺ salt, are available for clinical use in some countries outside the United States. Canrenone has a half-life of approximately 10 to 35 hours.The metabolites of spironolactone are excreted in both the urine and feces. New selective aldosterone receptor antagonists (SARA), such as eplerenone, have been developed but have not yet been introduced into clinical practice. Eplerenone and canrenone exhibit fewer steroidlike side effects (gynecomastia, hirsutism).