メチルドーパ 化學(xué)特性,用途語,生産方法
外観
白色～ほとんど白色粉末～結(jié)晶
解説
メチルドーパ，白色～帯灰白色の結(jié)晶性粉末．本品1 g は25 ℃ の水100 mL に溶ける．希塩酸に可溶，エタノールに難溶．約300 ℃ で分解する．λmax 281 nm(ε 2780)．[α]D23"－3.0±0.5°．カテコールアミンの前駆體である3,4-ジヒドロキシフェニルアラニン(DOPA)のα-メチル體である．降圧薬．高血圧癥，腎性高血圧癥に有効である．
森北出版「化學(xué)辭典（第2版）
用途
α受容體遮斷薬降圧効果
製造
α-(3,4-ジメトキシフェニル)アセトニトリルから數(shù)工程の反応を経て合成されたラセミ體から，L-メチルドーパを分離すると得られるメチルドーパ．
効能
血圧降下薬, α2アドレナリン受容體作動薬
説明
Methyldopa is an α-methoxylated derivative of levodopa that exhibits hypotensive action
by reducing overall peripheral vascular resistance and reducing heart work.
Antihypertensive action of methyldopa consists of the biotransformation of methyldopa
into methylnoradrenaline (methylnorepinephrine), which acts as a “pseudo neurotransmitter.”
The current, universally accepted point of view is that the action of methyldopa is carried
out through the CNS, where methylnorepinephrine, a powerful stimulant of
α-adrenergic receptors of the medulla, inhibits the vasomotor center.
使用
L-(-)-a-Methyldopa is an anti-Parkinson’s drug that has been used in anti-Parkinson’s mixtures.
定義
ChEBI: A derivative of L-tyrosine having a methyl group at the alpha-position and an additional hydroxy group at the 3-position on the phenyl ring.
生物學(xué)の機(jī)能
The spectrum of activity of α-methyldopa (Aldomet)
lies between those of the more potent agents, such as
guanethidine, and the milder antihypertensives, such as
reserpine. α-Methyldopa is a structural analogue of dihydroxyphenylalanine
(dopa) and differs from dopa
only by the presence of a methyl group on the -carbon
of the side chain.
一般的な説明
Methyldopa differs structurally from L-DOPA only in the presence of a -methyl group. Originally synthesized as an AADC inhibitor,methyldopa ultimately decreases the concentration of DA,NE, E, and serotonin in the CNS and periphery. However,its mechanism of action is not caused by its inhibition ofAADC but, rather, by its metabolism in the CNS to its activemetabolite ( β-methylnorepinephrine). Methyldopa istransported actively into CNS via an aromatic amino acidtransporter, where it is decarboxylated by AADC in thebrain to (1R,2S)- α-methyldopamine. This intermediate, inturn, is stereospecifically β-hydroxylated by DBH to givethe (1R,2S)-α-methylnorepinephrine. This active metaboliteis a selective α2-agonist because it has correct(1R,2S) configuration . It is currently postulated that α-methylnorepinephrine acts on α2-receptors in theCNS in the same manner as clonidine, to decrease sympatheticoutflow and lower blood pressure.
空気と水の反応
Very hygroscopic. Slightly water soluble. May be sensitive to prolonged exposure to air and light. The stability of aqueous solutions is markedly dependent on pH, oxygen and the amount of initial reactant. Aqueous solutions are stable for up to 50 hours in acid and neutral pH (6.2). At pH 8.0, decomposition products are formed in 3 to 5 hours. Solutions develop a red tint that becomes progressively darker (eventually forming a black precipitate).
反応プロフィール
Methyldopa undergoes catalytic oxygenation in the presence of magnesium, cupric, cobalt, nickel and ferric ions . A weakly acidic amino acid.
火災(zāi)危険
Flash point data for Methyldopa are not available; however, Methyldopa is probably combustible.
生物活性
L-aromatic amino acid decarboxylase inhibitor. Antihypertensive.
作用機(jī)序
A number of theories have been put forward to account
for the hypotensive action of α-methyldopa. Current
evidence suggests that for α-methyldopa to be an antihypertensive
agent, it must be converted to α-methylnorepinephrine;
however, its site of action appears to be
in the brain rather than in the periphery. Systemically administered
α-methyldopa rapidly enters the brain,
where it accumulates in noradrenergic nerves, is converted
to α-methylnorepinephrine, and is released.
Released α-methylnorepinephrine activates CNS α-
adrenoceptors whose function is to decrease sympathetic
outflow. Why α-methylnorepinephrine decreases sympathetic
outflow more effectively than does the naturally
occurring transmitter is not entirely clear.
薬物動態(tài)學(xué)
The oral bioavailability of methyldopa ranges from 20 to 50% and varies among individuals. Optimum blood pressure
response occurs in 12 to 24 hours in most patients. After withdrawal of the drug, blood pressure returns to
pretreatment levels within 24 to 48 hours. Methyldopa and its metabolites are weakly bound to plasma proteins.
Although 95% of a dose of methyldopa is eliminated in hypertensive patients with normal renal function, with a plasma
half-life of approximately 2 hours, in patients with impaired renal function the half-life is doubled to approximately 3 to
4 hours, with about 50% of it excreted. Orally administered methyldopa undergoes presystemic first-pass metabolism in
the gastrointestinal (GI) tract to its 3-O-monosulfate metabolite. Sulfate conjugation occurs to a greater extent when
the drug is given orally than when it is given intravenously (IV). Its rate of sulfate conjugation is decreased in patients
with renal insufficiency. Methyldopa is excreted in urine as its mono-O-sulfate conjugate. Any peripherally
decarboxylated α-methylnorepinephrine is metabolized by catecho-o-methyltransferase (COMT) and monoamine
oxidase (MAO).
Methyldopate is slowly hydrolyzed in the body to form methyldopa. The hypotensive effect of IV methyldopate begins in
4 to 6 hours and lasts 10 to 16 hours.
薬理學(xué)
The primary hemodynamic alteration responsible for
the hypotensive effects of α-methyldopa remains in dispute.
When the patient is supine, the reduction in blood
pressure produced by α-methyldopa correlates best
with a decrease in peripheral vascular resistance, cardiac
output being only slightly reduced. When the patient
is upright, the fall in blood pressure corresponds
more closely with a reduced cardiac output.
An important aspect of α-methyldopa’s hemodynamic
effects is that renal blood flow and glomerular filtration
rate are not reduced. As occurs with most sympathetic
depressant drugs and vasodilators, long-term
therapy with α-methyldopa leads to fluid retention,
edema formation, and plasma volume expansion.While
data conflict somewhat, it is generally thought that -
methyldopa suppresses plasma renin activity.
臨床応用
α-Methyldopa is not generally believed to be suitable
for monotherapy of primary hypertension. Because
plasma volume increases as the duration of α-methyldopa
therapy is extended, the drug should be used in
conjunction with a diuretic; this will produce a significantly
greater fall in blood pressure than would occur
with either drug used alone. Because α-methyldopa lowers
blood pressure without compromising either renal
blood flow or the glomerular filtration rate, it is particularly
valuable in hypertension complicated by renal disease.
However, if end-stage renal failure accompanies severe
hypertension,α-methyldopa may not be effective.
The presence of α-methyldopa and its metabolites
in the urine reduces the diagnostic value of urinary catecholamine
measurements as an indicator of pheochromocytoma,
since these substances interfere with the fluorescence
assay for catecholamines.
副作用
The most commonly encountered side effects of α-
methyldopa are sedation and drowsiness.These CNS effects
are probably the result of reductions in brain catecholamine
levels. Other side effects, also typical of
sympathetic depression, are dry mouth, nasal congestion,
orthostatic hypertension, and impotence.
Autoimmune reactions associated with α-methyldopa
treatment include thrombocytopenia and leukopenia.
Since a few cases of an α-methyldopa–induced hepatitis
have occurred, the drug is contraindicated in
patients with active hepatic disease. Flulike symptoms
also are known to occur.
安全性プロファイル
Poison by
intraperitoneal route. Moderately toxic by
ingestion and intravenous routes. Human
systemic effects by ingestion: fasciculations,
hallucinations, distorted perceptions,
tremors, allergic dermatitis, necrotic
gastrointestinal changes. An experimental
teratogen. Human reproductive effects:
menstrual cycle changes or disorders, effects
on newborn including abnormal neonatal
measures and growth statistics, biochemical
and metabolic changes. Experimental reproductive effects. Mutation data
reported. When heated to decomposition it
emits toxic fumes of NOx
代謝
Approximately 50% of an orally administered dose of
α-methyldopa is absorbed from the gastrointestinal
tract. Both peak plasma drug levels and maximal blood
pressure–lowering effects are observed 2 to 6 hours after
oral administration. A considerable amount of unchanged
α-methyldopa and several conjugated and decarboxylated
metabolites can be found in the urine.
純化方法
Recrystallise methyldopa from H2O. [Reinhold et al. J Org Chem 33 1209 1968.] The L-isomer forms a sesquihydrate from H2O m 302-304o (dec), and the anhydrous crystals are hygroscopic,[] 23D -4.0o (c 1, 0.1N HCl), []546 +154.5o (c 5, CuSO4 solution). It has max at 281nm ( 2780). Its solubility in H2O at 25o is ~10mg/mL and the pH of an aqueous solution is ~5.0. It is insoluble in most organic solvents. [Stein et al. J Am Chem Soc 77 700 1955, Beilstein 4 IV 2505.]
メチルドーパ 上流と下流の製品情報
原材料
準(zhǔn)備製品