キニジン 化学特性,用途語,生産方法
外観
白色～ほとんど白色, 結晶～粉末
性質
キニジンの融点は174°Cで、常温で固体です。メタノールに非常に溶けやすく、アルコールやエーテル、クロロホルムに溶け、石油エーテルには不溶です。
酸の強さを定量的に表すための指標の1つである酸解離定数 (pKa) は8.56となっています。なお、pKa が小さいほど強い酸であることを示します。
溶解性
溶媒 : アルコール, エーテル, クロロホルムエタノール(99.5)に溶ける。
解説
C20H24N2O2(324.41)．キニジンは，キナアルカロイドの一つ．キニーネの立体異性体．結晶．融点174～175 ℃(無水物)．[α]15D＋230°(クロロホルム)．[α]17D＋258°(エタノール)．pK1 5.4．pK2 10.0．水に難溶，エタノール，エーテル，クロロホルムに可溶，メタノールに易溶．希硫酸溶液は青色の蛍光を発する．LD50 21.6 mg/kg(ネコ，静脈)．森北出版「化学辞典（第2版）
用途
薬理研究用試薬、光学分割剤。
製造法
現在、販売されているキニジンの多くは、キニーネの異性化により製造されています。天然からは、シナ属の抽出物よりキニーネを除去後、残った母液から得られます。水中やアルコール中で、再結晶による精製が可能です。
医薬用
不整脈治療剤。南アメリカ原産アカネ科のキナノキ類樹皮に含まれるアルカロイド。マラリア治療薬キニーネの異性体である。硫酸塩の形で用いる。心筋抑制作用，すなわち心筋の興奮性および収縮力減弱，不応期延長作用があり，異所的刺激発生を減少させる。アトロピン様の作用も有し，拍動を促進するが，この作用は弱い。心房細動，粗動の治療に有効である。心室内刺激伝導系障害，僧帽弁狭窄症，ジギタリス過量投与時などには禁忌とされている。副作用は，キニーネと同様に悪心，嘔吐，視力障害などのほか，過敏性反応をきたすこともある。心筋に対する作用の結果，心室性不整脈をきたして死亡することもあるので注意を要する。
効能
抗不整脈薬, 抗マラリア薬, ナトリウムチャネル遮断薬
説明
Quinidine is a commonly used class I antiarrhythmic drug. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree. It exerts its antiarrhythmic effects on the heart by interacting with the electrophysiology mechanisms that cause arrhythmias to modify the abnormalities in impulse initiation and conduction. Quinidine depresses normal automaticity in cardiac fibers that may act as ectopic pacemakers causing arrhythmias. Quinidine also blocks the slowly inactivating, tetrodotoxin-sensitive Na current, the slow inward calcium current (ICa), the rapid (IKr) and slow (IKs) components of the delayed potassium rectifier current, the inward potassium rectifier current (IKI), the ATP-sensitive potassium channel (IKATP) and Ito.
化学的特性
white to light yellow crystal powde
物理的性質
Appearance: Quinidine is commonly used in its sulfate form with white needle-like
crystal and bitter smell. It changes color easily when exposed to light. Solubility: It
was soluble in ethanol and chloroform. Its water solubility is 0.05?g/100?mL (20?°C).
Specific optical rotation: 256°
(c?=?1, EtOH). Melting point: 168–172?°C.
来歴
In 1820, the French chemists Pierre Pelletier and Joseph Caventou extracted some
alkaloids from the cinchona bark, including quinine and quinidine. Subsequently,
quinine was demonstrated to play a very important role in the treatment of malaria after a number of scientific researches. Quinidine is the dextroisomer of quinine and
has the similar pharmacological properties as quinine, but quinidine’s effects are
five to ten times stronger on the heart than quinine.
使用
Quinidine occurs in cinchona bark to about0.25–0.3% and also in cuprea bark. It is present in quinine sulfate mother liquor. Itis formed by isomerization of quinine. Itis used in the prevention of certain cardiacarrhythmias.
適応症
Quinidine acts as a class I antiarrhythmic agent (Ia) in the heart. It was clinically
applicable to the treatment of recurrent, documented, life-threatening ventricular
arrhythmias .
定義
ChEBI: A cinchona alkaloid consisting of cinchonine with the hydrogen at the 6-position of the quinoline ring substituted by methoxy.
生物学の機能
Quinidine is an alkaloid obtained from various species
of Cinchona or its hybrids, from Remijia pedunculata, or
from quinine. Quinidine is the dextrorotatory isomer of
quinine.Quinidine (Quinidex) was one of the first clinically
used antiarrhythmic agents. Because of the high incidence
of ventricular proarrhythmia associated with its
use and numerous other equally efficacious agents,
quinidine is now used sparingly. Quinidine shares all of
the pharmacological properties of quinine, including antimalarial,
antipyretic, oxytocic, and skeletal muscle relaxant
actions.
一般的な説明
Crystals or white powder.
空気と水の反応
Insoluble in water.
危険性
Poison.
健康ハザード
Quinidine is more potent than quinine in itsaction on the cardiovascular system. Overdosesmay cause lowering of blood pressure.Gastric effects are lower than quinine. Toxicityis lower relative to quinine; subcutaneouslethal dose in mice is 400 mg/kg against200 mg/kg for quinine.
火災危険
Flash point data for Quinidine are not available. Quinidine is probably combustible.
法規情報
危険物船舶運送及び貯蔵規則にて、毒物類・毒物 (危規則第3条危険物告示別表第1) に指定されています。また、航空法にて、毒物類・毒物 (施行規則第194条危険物告示別表第1) に指定されています。
使用用途
キニジンは、キナ属の樹皮から抽出されるアルカロイドです。
1. 医薬品分野
強力な抗不整脈作用を有しているため、古くから医薬品分野において心房および心室性不整脈の治療薬として使用されてきました。
2. 抗マラリア作用
寄生虫の酸性食液胞内でヘムポリマー (ヘマゾイン) と結合し、ヘムポリマーゼ酵素による重合を阻害することにより、主に赤血球内分裂薬として作用して抗マラリア活性を発揮します。
3. 禁忌
刺激伝導障害や重篤なうっ血性心不全、高カリウム血症の症状を持つ患者には禁忌のため、使用できません。他にも併用禁止薬が多数報告されています。
4. 化試薬
シャープレス不斉ジヒドロキシ化試薬のAD-mix-βには、キニジン誘導体がリガンドとして使用されています。
取り扱い及び保管上の注意
取り扱う場合
強酸化剤との接触を避けます。局所排気装置であるドラフトチャンバー内で使用し、個人用保護具を着用します。
火災の場合
キニジンは不燃性で、それ自体が燃えることはありません。ただし、熱分解で窒素酸化物のガスを発生するおそれがあります。消火には水噴霧や泡消火剤、乾燥砂などを使用します。
皮膚に付着した場合
皮膚に付着しないよう注意が必要です。使用時は、必ず白衣や作業着などの保護衣や保護手袋を着用します。保護衣の袖は決して捲らず、皮膚が暴露しないようにします。
眼に入った場合
使用時は、必ず保護メガネまたはゴーグルを着用します。万が一眼に入った場合は、水で数分間注意深く洗います。ただちに、医師の診察が必要です。
保管する場合
保管する際は、遮光性のガラス製容器に入れて密閉します。直射日光を避け、換気がよく、なるべく涼しい場所は望ましいです。
薬理学
Quinidine exhibits all of the pharmacological properties of quinine, including antimalarial, fever-reducing, and other properties. Quinidine is used in various forms of arrhythmia for preventing tachycardia and atrial fibrillation, and particularly for preventing ciliary fibrillation, paroxysmal supraventricular tachycardia, extrasystole, and ventricular tachycardia. However, it is a toxic drug and is used relatively rarely. It is also prescribed under the name cardioquin, duraquin, quinidex, and others.
臨床応用
Primary indications for the use of quinidine include (1) abolition of premature complexes that have an atrial, A-V junctional, or ventricular origin; (2) restoration of normal sinus rhythm in atrial flutter and atrial fibrillation after controlling the ventricular rate with digitalis; (3) maintenance of normal sinus rhythm after electrical conversion of atrial arrhythmias; (4) prophylaxis against arrhythmias associated with electrical countershock; (5) termination of ventricular tachycardia; and (6) suppression of repetitive tachycardia associated with Wolff- Parkinson-White (WPW) syndrome.
Although quinidine often is successful in producing normal sinus rhythm, its administration in the presence of a rapid atrial rate (flutter and possibly atrial fibrillation) can lead to a further and dangerous increase in the ventricular rate secondary to inhibition of basal vagal tone upon the A-V node. For this reason, digitalis should be used before quinidine when one is attempting to convert atrial flutter or atrial fibrillation to normal sinus rhythm.
安全性プロファイル
Poison by ingestion, subcutaneous, intravenous, intramuscular, and intraperitoneal routes. A skin irritant. Implicated in aplastic anemia. When heated to decomposition it emits toxic fumes of NOx.
薬物相互作用
Quinidine can increase the plasma concentrations of
digoxin, which may in turn lead to signs and symptoms of
digitalis toxicity. Gastrointestinal, central nervous system
(CNS), or cardiac toxicity associated with elevated
digoxin concentrations may occur.Quinidine and digoxin
can be administered concurrently; however, a downward
adjustment in the digoxin dose may be required.
Drugs that have been associated with elevations in
quinidine concentrations include acetazolamide, the
antacids magnesium hydroxide and calcium carbonate,
and the H2-receptor antagonist cimetidine. Cimetidine
inhibits the hepatic metabolism of quinidine. Phenytoin,
rifampin, and barbiturates increase the hepatic metabolism
of quinidine and reduce its plasma concentrations.
代謝
Quinidine's bioavailability appears to depend on a combination of metabolism and P-gp efflux. The
bioavailabilities of quinidine sulfate and gluconate are 80 to 85% and 70 to 75%, respectively. Once
absorbed, quinidine is subject to hepatic first-pass metabolism and is approximately 85% plasma
protein bound, with an elimination half-life of approximately 6 hours. Quinidine is metabolized mainly
in the liver, and renal excretion of unchanged drug also is significant (~10–50%). The metabolites
are hydroxylated derivatives at either the quinoline ring through first-pass O-demethylation or at the
quinuclidine ring through oxidation of the vinyl group. These metabolites possess only about
one-third the activity of quinidine. Their contribution to overall therapeutic effect of quinidine is
unclear. Recently, the clinical significance of the well-documented digoxin–quinidine interaction was
described previously under digoxin–drug interactions. Apparently, quinidine (a P-gp substrate)
inhibits the renal tubular secretion of digoxin via the P-gp efflux pump, resulting in increased plasma
concentration for digoxin.
純化方法
Crystallise it from *C6H6 or dry CHCl3/pet ether (b 40-60o), discarding the initial, oily crop of crystals. Dry it under vacuum at 100o over P2O5. It has been used as a chiral catalyst [Wynberg & Staring J Am Chem Soc 104 166 1982, J Org Chem 50 1977 1985]. [Beilstein 23 H 506, 23 I 164, 23 II 414, 23 III/IV 3261, 23/13 V 395.]
予防処置
One of the few absolute contraindications for quinidine
is complete A-V block with an A-V pacemaker or idioventricular
pacemaker; this may be suppressed by
quinidine, leading to cardiac arrest.
Persons with congenital QT prolongation may develop
torsades de pointes tachyarrhythmia and should
not be exposed to quinidine.
Owing to the negative inotropic action of quinidine,
it is contraindicated in congestive heart failure and hypotension.
Digitalis intoxication and hyperkalemia can accentuate
the depression of conduction caused by quinidine.
Myasthenia gravis can be aggravated severely by
quinidine’s actions at the neuromuscular junction.
The use of quinidine and quinine should be avoided
in patients who previously showed evidence of quinidine-
induced thrombocytopenia.
参考文献
Wit, Andrew L. "The Effects of Quinidine on the Cellular Electrophysiology of the Heart: A Brief Review." Journal of Cardiovascular Electrophysiology 3.5(2010):316-322.
Alloway, J. A., and M. P. Salata. "Quinidine-induced rheumatic syndromes. " Seminars in Arthritis & Rheumatism 24.5(1995):315-322.
Nakano, J, and M. C. R. Jr. "Effect of quinidine on cardiovascular dynamics." Arch Int Pharmacodyn Ther 168.2(1967):400-416.
キニジン 上流と下流の製品情報
原材料
準備製品