グアネチジン硫酸塩 化学特性,用途語,生産方法
外観
本品は白色の結晶又は結晶性の粉末で，においはないか，
又はわずかに特異なにおいがあり，味は苦い．
本品はギ酸に極めて溶けやすく，水に溶けやすく，エタノ
ール(95)又はジエチルエーテルにほとんど溶けない．
融点：251～256℃(減圧毛細管，分解)．
効能
血圧降下薬, ノルアドレナリン遊離抑制薬
確認試験
(１) 本品の水溶液(1→4000)4mLに1－ナフトール試液
2mL，ジアセチル試液1mL及び水15mLを加え，30分間放
置するとき，液は赤色を呈する．
(２) 本品を乾燥し，赤外吸収スペクトル測定法〈2.25〉の
臭化カリウム錠剤法により試験を行い，本品のスペクトルと
本品の参照スペクトルを比較するとき，両者のスペクトルは
同一波数のところに同様の強度の吸収を認める．
(３) 本品の水溶液(1→10)は硫酸塩の定性反応〈1.09〉を呈
する．
定量法
本品を乾燥し，その約0.5gを精密に量り，ギ酸2mL
に溶かした後，無水酢酸／酢酸(100)混液(6：1)70mLを加え，
0.1mol/L過塩素酸で滴定〈2.50〉する(電位差滴定法)．同様の
方法で空試験を行い，補正する．
純度試験
(１) 溶状 本品1.0gを水50mLに溶かすとき，液は無色澄
明である．
(２) 硫酸メチルイソチオ尿素 本品2.0gを水酸化ナトリウ
ム試液80mLに溶かし，10分間放置する．次に塩酸60mL，
臭化ナトリウム2g及び水を加えて溶かし，200mLとし，1／60
mol/L臭素酸カリウム液0.70mL及びヨウ化亜鉛デンプン試
液2mLを加えるとき，液の色は青色である．
(３) 重金属〈1.07〉 本品2.0gをとり，第4法により操作し，
試験を行う．比較液には鉛標準液2.0mLを加える(10ppm以
下)．
貯法
保存条件 遮光して保存する．
容器 気密容器．
乾燥減量
0.5％以下(1g，105℃，4時間)．
強熱残分
0.2％以下(1g)．
解説
グアネチジン硫酸塩，ヘプタメチレンイミンとクロロアセトニトリルから生成したニトリルを還元したのち，S-メチルイソチオ尿素硫酸塩と反応させると得られる．分解点251～256 ℃．水に易溶，エタノールに不溶．交感神経末梢伝達遮断による血管拡張，血圧降下剤として使用される．LD50 1000 mg/kg(ラット，経口)．
説明
Guanethidine is an antihypertensive compound that competes with norepinephrine for transport into presynaptic terminals of adrenergic neurons by the norepinephrine transporter. Once guanethidine has entered the nerve, it becomes concentrated in synaptic vesicles, depleting endogenous norepinephrine, and thus, reducing the release of norepinephrine in response to action potentials. Guanethidine’s actions are restricted to peripheral nerve terminals because its basic guanidine group does not allow passage through the blood brain barrier. Its use has been explored in the relief of chronic pain caused by complex regional pain syndrome.
化学的特性
GUANETHIDINE SULFATE is colourless, crystalline powder
使用
Antihypertensive.
定義
ChEBI: A organic sulfate salt obtained from guanethidine and sulfuric acid in a 1:1 ratio.
一般的な説明
Guanethidinemonosulfate, [2-(hexahydro-1 (2H)-azocinyl)ethyl]guanidinesulfate (Ismelin sulfate), is a white, crystalline materialthat is very soluble in water. It was one of a series ofguanidine compounds prepared in the search for potent antitrypanosomalagents. There is an absence of CNS effects,such as depression, because the drug is highly polar anddoes not easily cross the blood-brain barrier. Guanethidinemonosulfate produces a gradual, prolonged fall in bloodpressure. Usually, 2 to 7 days of therapy are required beforethe peak effect is reached, and usually, this peak effectis maintained for 3 or 4 days. Then, if the drug is discontinued,the blood pressure returns to pretreatment levelsover a period of 1 to 3 weeks. Because of this slow onsetand prolonged duration of action, only a single daily doseis needed.
作用機序
Guanethidine is an adrenergic neuronal blocking agent that produces a selective block of peripheral sympathetic
pathways by replacing and depleting norepinephrine stores from adrenergic nerve endings, but not from the adrenal
medulla. It prevents the release of norepinephrine from adrenergic nerve endings in response to sympathetic
nerve stimulation. The chronic administration of guanethidine results in an increased sensitivity of these effector cells
to catecholamines. Following the oral administration of usual doses of guanethidine, depletion of the catecholamine
stores from adrenergic nerve endings occurs at a very slow rate, producing a more gradual and prolonged fall in
systolic blood pressure than in diastolic pressure. Associated with the decrease in blood pressure is an increase in
sodium and water retention and expansion of plasma volume (edema). If a diuretic is not administered concurrently with
guanethidine, tolerance to the antihypertensive effect of the guanethidine during prolonged therapy can result.
薬物動態学
Guanethidine is incompletely absorbed from the GI tract and is metabolized in the liver to several metabolites,
including guanethidine N-oxide (from flavin mononucleotide). These metabolites of guanethidine are excreted in the
urine and have less than 10% of its hypotensive activity. The amount of drug that reaches the systemic circulation
after oral administration is highly variable from patient to patient and may range from 3 to 50% of a dose. Guanethidine
accumulates in the neurons with an elimination half-life of 5 days.
臨床応用
Guanethidine monosulfate is metabolized by microsomalenzymes to 2-(6-carboxyhexylamino)ethylguanidine andguanethidine N-oxide . Both metabolites havevery weak antihypertensive properties. Guanethidine monosulfateis taken up by the amine pump located on theneuronal membrane and retained in the nerve, displacingnorepinephrine from its storage sites in the neuronal granules.The displaced norepinephrine is metabolized to homovanillicacid by mitochondrial MAO, depleting the nerveending of the neurotransmitter. The usefulness of guanethidinemonosulfate also resides in the fact that once it is takenup by the nerve, it produces a sympathetic blockade by inhibitingrelease of nonepinephrine that would occur on neuronalmembrane response to stimulation29 by the nerveaction potential. Guanethidine monosulfate stored in thegranules is released by the nerve action potential but hasvery low intrinsic activity for the adrenergic receptors on thepostjunctional membrane. Moderate doses for a prolongedperiod or large doses may produce undesirable side effectsby causing neuromuscular blockade and adrenergic nerveconduction blockade.
副作用
Adverse effects of guanethidine frequently are dose related, including dizziness, weakness, lassitude, and syncope
resulting from postural or postexercise hypotension. A hot environment (i.e., a hot bath) may aggravate postural
hypotension. Patients should be warned about possible orthostatic hypotension and about the effect of rapid postural
changes on blood pressure (e.g., arising in the morning) that may cause fainting, especially during the initial period of
dosage adjustment. Sodium retention (edema) usually is controlled by the coadministration of a diuretic.
薬物相互作用
Diuretics and other hypotensive drugs can potentiate the hypotensive effects of guanethidine. Reportedly, MAO
inhibitors antagonize the hypotensive effect of guanethidine. Oral sympathomimetic, nasal decongestants, and other
vasopressor agents should be used cautiously in patients receiving guanethidine, because guanethidine may
potentiate their pressor effects. The mydriatic response to ophthalmic administration of phenylephrine is markedly
increased in patients receiving guanethidine either ophthalmically or orally.
Tricyclic antidepressants and some phenothiazines block the uptake of guanethidine into adrenergic neurons and,
thus, prevent the hypotensive activity of guanethidine. Orthostatic hypotension may be increased by concomitant
administration of alcohol with guanethidine, and patients receiving guanethidine should be cautioned to limit alcohol
intake.
グアネチジン硫酸塩 上流と下流の製品情報
原材料
準備製品