Метилдопа

Описание

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.

Использование

L-(-)-a-Methyldopa is an anti-Parkinson’s drug that has been used in anti-Parkinson’s mixtures.

Определение

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.

Биологические функции

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.

Общее описание

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.

Реакции воздуха и воды

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).

Профиль реактивности

Methyldopa undergoes catalytic oxygenation in the presence of magnesium, cupric, cobalt, nickel and ferric ions . A weakly acidic amino acid.

Пожароопасность

Flash point data for Methyldopa are not available; however, Methyldopa is probably combustible.

Биологическая активность

L-aromatic amino acid decarboxylase inhibitor. Antihypertensive.

Механизм действия

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.

Фармакокине?тика

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.

Фармаколо?гия

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.

Клиническое использование

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.

Побочные эффекты

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.

Профиль безопасности

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

Метаболизм

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.

Методы очистки

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.]