エピネフリン 化學特性,用途語,生産方法
外観
白色～うすい褐色, 粉末
種類
現(xiàn)在市販されているアドレナリン製品の種類には、主に臨床用の醫(yī)薬品と研究開発用試薬とがあります。臨床用の醫(yī)薬品は、主に注射剤として販売されている他、気管支喘息などの治療では吸入薬として用いられることもある薬剤です。
様々なメーカーから、様々な用量?濃度の製品が発売されており、適切なものが選ばれます。代表的な商品名は、「エピスタ」「ボスミン」「エピペン」です。いずれも処方箋が必要な薬剤です。
研究開発用では、輸送は室溫で良いものの冷蔵保管が必要な試薬として扱われます。1g , 5g , 10gなどの容量があります。キラル化合物ですが、通常市販されているものはR體です。また、塩酸塩も試薬として販売されています。
性質(zhì)
1) (血液，副腎皮質(zhì)，神経)，向交感神経性，血圧上昇，D體のみ有効
溶解性
薄めた塩酸に溶けるが水に極めて溶けにくく、エタノール、ジエチルエーテル及びクロロホルムにほとんど溶けない。
解説
L-アドレナリン，アドレナリンともいう．副腎髄質(zhì)，アドレナリン作動性ニューロンで合成され，ホルモンとしても，また神経伝達物質(zhì)としても作用する．高峰譲吉，上中啓三により1900年に結(jié)晶化され発見された最初のホルモン．
用途
感神経が興奮した狀態(tài)、すなわち「闘爭か逃走か (fight-or-flight)」のホルモンと呼ばれる。動物が敵から身を守る、あるいは獲物を捕食する必要にせまられるなどといった狀態(tài)に相當するストレス応答を、全身の器官に引き起こす。
合成
図2. アト?レナリンの生合成経路
アドレナリンはカテコールアミンの一つです。生合成経路では、L-チロシンからL-ドーパを経て順にドパミン、ノルアドレナリン (ノルエピネフリン) 、アドレナリン (エピネフリン) の順で合成されます。
応用
醫(yī)薬品としては交感神経興奮剤、血管収縮剤、血圧上昇剤として使われ、出血を止め、気管支喘息(ぜんそく)の発作を抑える。注射剤、塗布剤、スプレー剤などがある。繁用すると、不安、頭痛、心悸亢進(しんきこうしん)、不眠などの副作用が現(xiàn)れる。
効能
気管支拡張薬, 血管収縮薬, アドレナリン受容體作動薬
薬理作用
アドレナリンは、交感神経α及びβアドレナリン受容體に作用し、交感神経を興奮させる働きがあります。主な作用の例として下記のものが挙げられます。
- 心臓における強心作用: 心拍數(shù)、心筋収縮力及び心拍出量を増加させる (β1 刺激作用)?
- 皮膚及び粘膜の血管を収縮させる作用 (α1 刺激作用)?
- 骨格筋及び內(nèi)臓や心臓冠動脈の血管を拡張させる作用 (β2 刺激作用)?
- 気管支平滑筋を弛緩し、気管支を拡張させる作用 (β2 刺激作用)?
また、α遮斷作用のある薬との併用はアドレナリンの作用を逆転させ、急激な血圧降下を起こす可能性があるため禁忌とされています。具體的な薬剤の例としては、下記の抗精神病薬が挙げられます。
- ブチロフェノン系薬剤
- 系薬剤
- イミノジベンジル系薬剤
- ゾテピン
- セロトニン?ドパミン拮抗薬
- ドパミン受容體部分作動薬
尚、ここに記載されていない薬剤でも、α遮斷作用のある薬剤は原則的に併用禁忌です。ただし、アナフィラキシーショックの救急治療の際には、アドレナリンが投與される場合があります。
商品名
エピペン (マイランEPD); ボスミン (第一三共); ボスミン (第一三共)
使用上の注意
不活性ガス封入
説明
The combination of the catechol nucleus, the β-hydroxyl group, and the N-methyl give EPI a
direct action and a strong affinity for all adrenergic receptors. Epinephrine and all other
catechols are chemically susceptible to oxygen and other oxidizing agents, especially in the
presence of bases and light, quickly decomposing to inactive quinones. Therefore, all catechol
drugs are stabilized with antioxidants and dispensed in air-tight amber containers.
化學的特性
off-white powder
使用
Endogenous catcholamine with combined α-and β-agonist activity. Principal sympathomimetic hormone produced by the adrenal medulla. Bronchodilator; cardiostimulant; mydriatic; antiglaucoma.
調(diào)製方法
Epinephrine is synthesized in the body from the nonessential amino acid tyrosine. Tyrosineundergoes hydroxylation to produce DOPA (3,4-dihydroxyphenylalanine). DOPA decarboxylationproduces dopamine, which is hydroxylated to norepinephrine. Norepinephrine, whichis closely related to epinephrine, performs a number of similar functions in the body. The prefix “nor” associated with a compound is used to denote an alkylated nitrogen in the compoundthat has lost an alkyl group. It comes from the German N-ohne-radical, which means Nitrogenwithout the radical. Therefore norepinephrine is epinephrine minus the methyl, CH3, radicalon the nitrogen. The methylation of norepinephrine gives epinephrine.
定義
ChEBI: The R-enantiomer of adrenaline. It is a hormone secreted by the adrenal glands resulting in the 'fight-or-flight' response.
適応癥
Epinephrine administered subcutaneously is used to
manage severe acute episodes of bronchospasm and
status asthmaticus. In addition to its bronchodilator activity
through β-adrenoceptor stimulation, a portion of
the therapeutic utility of epinephrine in these acute settings
may be due to a reduction in pulmonary edema as
a result of pulmonary vasoconstriction, the latter effect
resulting from α-adrenoceptor stimulation.
世界保健機関（WHO）
Epinephrine, first isolated in 1899, is the main hormone secreted
by the adrenal medulla. It is widely used as a vasoconstrictor substance and in the
treatment of anaphylactic shock. Its use in combination with local anaesthetics to
prolong infiltration anaesthesia has been associated with systemic reactions
including serious cardiovascular and cerebrovascular incidents. Regulations
restricting the concentrations permitted in such preparations have been introduced
in many countries but combination products containing epinephrine or levarterenol
in concentrations of 1:80,000 or less remain widely available. Representative
preparations are included in the WHO Model List of Essential Drugs.
(Reference: (WHTAC1) The Use of Essential Drugs, 2nd Report of the WHO Expert
Committee, 722, , 1985)
生物學の機能
Epinephrine is found only in very low concentrations in
the mammalian CNS, and it is unlikely to play a major
role as a neurotransmitter.
一般的な説明
White to nearly-white microcrystalline powder or granules. Odorless. Melting point 211-212°C. Aqueous solutions are slightly alkaline. Slightly bitter, numbing taste.
空気と水の反応
L(-)-Epinephrine darkens slowly on exposure to air and light. Water insoluble. Readily soluble in aqueous solutions of inorganic acids. Solutions undergo oxidation in the presence of oxygen.
反応プロフィール
L(-)-Epinephrine is incompatible with oxidizers, alkalis, copper, iron, silver, zinc and other metals; gum and tannin. L(-)-Epinephrine is also incompatible with acids, acid chlorides and acid anhydrides. L(-)-Epinephrine reacts with salts of sulfurous acid .
火災危険
Flash point data for L(-)-Epinephrine are not available. L(-)-Epinephrine is probably combustible.
使用用途
アドレナリンは、體內(nèi)でホルモンとして分泌されているだけではなく、醫(yī)薬品として製造販売されています。臨床用製剤の主な効能?効果には、下記のようなものがあります。特にアナフィラキシー反応に対する治療については、自己注射も可能であり、発癥する懸念がある人に処方されています。
- 蜂毒、食物及び薬物等に起因するアナフィラキシー反応に対する補助治療
- 気管支喘息、百日咳の気管支痙攣の緩解
- 急性低血圧又はショック時の補助治療、心停止の補助治療
- 局所麻酔薬の作用の延長
- 手術(shù)時の局所出血の予防と治療
- 耳鼻咽頭科における局所出血及び粘膜の充血?腫脹の治療
- 外創(chuàng)における局所出血の治療
- 歯科治療における浸潤麻酔又は伝達麻酔
臨床以外の用途では、研究開発用試薬として有機合成化學や生化學の分野で使用される場合があります。
作用機序
The effects on pulmonary function are quite rapid, with peak effects
occurring within 5 to 15 minutes. Measurable improvement
in pulmonary function is maintained for up
to 4 hours.The characteristic cardiovascular effects seen
at therapeutic doses of epinephrine include increased
heart rate, increased cardiac output, increased stroke
volume, an elevation of systolic pressure and decrease
in diastolic pressure, and a decrease in systemic vascular
resistance. The cardiovascular response to epinephrine
represents the algebraic sum of both α- and β-adrenoceptor
stimulation. A decrease in diastolic blood pressure
and a decrease in systemic vascular resistance are
reflections of vasodilation, a β2-adrenoceptor response.
The increase in heart rate and systolic pressure is the result
of either a direct effect of epinephrine on the myocardium,
primarily a β1 effect, or a reflex action provoked
by a decrease in peripheral resistance, mean
arterial pressure, or both. Overt α-adrenoceptor effects,
such as systemic vasoconstriction, are not obvious unless
large doses are used.
臨床応用
The ability of epinephrine to stimulate β2-receptors hasled to its use by injection and by inhalation to relaxbronchial smooth muscle in asthma and in anaphylacticreactions. Several OTC preparations (e.g., Primatene, Bronkaid)used for treating bronchial asthma use E. It is also usedin inhibiting uterine contraction. Because of its α-activity, Eis used to treat hypotensive crises and nasal congestion, toenhance the activity of local anesthetics, and as a constrictorin hemorrhage.
In addition, E is used in the treatment of open-angle glaucoma,where it apparently reduces intraocular pressure byincreasing the rate of outflow of aqueous humor from theanterior chamber of the eye. The irritation often experiencedon instillation of E into the eye has led to the developmentof other preparations of the drug that potentially are not asirritating. One such example is dipivefrin.
副作用
Patients treated with recommended dosages of epinephrine
will complain of feeling nervous or anxious.
Some will have tremor of the hand or upper extremity
and many will complain of palpitations. Epinephrine is
dangerous if recommended dosages are exceeded or if
the drug is used in patients with coronary artery disease,
arrhythmias, or hypertension. The inappropriate use of
epinephrine has resulted in extreme hypertension and
cerebrovascular accidents, pulmonary edema, angina,
and ventricular arrhythmias, including ventricular fibrillation.
At recommended dosages, adverse effects from inhaled
isoproterenol are infrequent and not serious.
When excessive dosages are used, tachycardia, dizziness,
and nervousness may occur, and some patients
may have arrhythmias.
安全性プロファイル
Human poison by
subcutaneous route. Experimental poison by
ingestion, skin contact, subcutaneous,
intraperitoneal, intravenous, and
intramuscular routes. Human systemic
effects: cardiomyopathy includmg infarction,
arrhythmias. An experimental teratogen.
Experimental reproductive effects. Mutation
data reported. When heated to
decomposition it emits toxic fumes of NOx.
Used as an adrenergic, sympathomimetic,
vasoconstrictor, bronchodilator, and cardiac
stimulant.
代謝
Epinephrine is ultimately metabolized by COMT and MAO to 3-methoxy-4-hydroxy-mandelic acid
(vanillylmandelic acid), which is excreted as the sulfate or glucuronide in the urine.
Only a very small amount is excreted unchanged.
純化方法
L-Adrenaline has been recrystallised from EtOH/AcOH/NH3 [Jensen J Am Chem Soc 57 1765 1935]. Itis sparingly soluble in H2O, readily in acidic or basic solutions but insoluble in aqueous NH3, alkali carbonate solutions, EtOH, CHCl3, Et2O or Me2CO. It has also been purified by dissolving in dilute aqueous acid, then precipitating it by adding dilute aqueous ammonia or alkali carbonates. It is readily oxidised in air and turns brown on exposure to light and air. (Epinephrine readily oxidises in neutral alkaline solution. This can be diminished if a little sulfite is added). Store it in the dark under N2. [Lewis Br J Pharmacol Chemother 9 488 1954]. The hydrogen oxalate salt has m 191-192o(dec, evacuated capillary) after recrystallisation from H2O or EtOH [Pickholz J Chem Soc 928 1945]. [Beilstein 13 H 830, 13 III/IV 2927.]
エピネフリン 上流と下流の製品情報
原材料
準備製品