Methyldopa

Absorption

Methyldopa is incompletely absorbed from the gastrointestinal tract following oral administration. In healthy individuals, the inactive D-isomer is less readily absorbed than the active L-isomer. The mean bioavailability of methyldopa is 25%, ranging from eight to 62%. Following oral administration, about 50% of the dose is absorbed and Tmax is about three to six hours.

Toxicity

The lowest published toxic dose via oral route is 44 gm/kg/3Y (intermittent) in a female. Oral LD50 is 5000 mg/kg in rats and 5300 mg/kg in mice. Intraperitoneal LD50 is 300 mg/kg in rats and 150 mg/kg in mice.
Acute overdosage is characterized by acute hypotension and other presentations attributed to the brain and gastrointestinal dysfunction, such as excessive sedation, weakness, bradycardia, dizziness, light-headedness, constipation, distention, flatus, diarrhea, nausea, and vomiting. Symptomatic and supportive measures should be initiated in the event of methyldopa overdose. Overdosage following recent oral ingestion can be managed by gastric lavage or emesis, as well as infusions to limit further drug absorption. Cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity should be closely monitored. The use of sympathomimetic drugs such as levarterenol, epinephrine, and metaraminol bitartrate, or dialysis may be considered.

Description

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.

Originator

Aldometil,MSD,W. Germany,1962

The Uses of Methyldopa

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

The Uses of Methyldopa

Antihypertensor;L-aromatic aminoacid decarboxylase inhibitor

The Uses of Methyldopa

vitamin, coenzyme B12

The Uses of Methyldopa

It is prescribed for arterial hypertension and hypertensive crises.

Indications

Methyldopa is indicated for the management of hypertension as monotherapy or in combination with hydrochlorothiazide. Methyldopa injection is used to manage hypertensive crises.

Background

Methyldopa, or α-methyldopa, is a centrally acting sympatholytic agent and an antihypertensive agent. It is an analog of DOPA (3,4‐hydroxyphenylanine), and it is a prodrug, meaning that the drug requires biotransformation to an active metabolite for therapeutic effects. Methyldopa works by binding to alpha(α)-2 adrenergic receptors as an agonist, leading to the inhibition of adrenergic neuronal outflow and reduction of vasoconstrictor adrenergic signals. Methyldopa exists in two isomers D-α-methyldopa and L-α-methyldopa, which is the active form.
First introduced in 1960 as an antihypertensive agent, methyldopa was considered to be useful in certain patient populations, such as pregnant women and patients with renal insufficiency. Since then, methyldopa was largely replaced by newer, better-tolerated antihypertensive agents; however, it is still used as monotherapy or in combination with hydrochlorothiazide. Methyldopa is also available as intravenous injection, which is used to manage hypertension when oral therapy is unfeasible and to treat hypertensive crisis.

What are the applications of Application

L-(?)-α-Methyldopa is a DDC inhibitor and antihypertensive

Definition

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.

Manufacturing Process

The dl-α-methyl-3,4-dihydroxyphenylalanine may be made as described in US Patent 2,868,818. Five-tenths of a gram of 3-hydroxy-4- methoxyphenylalaninewas dissolved in 20 ml of concentrated hydrochloric acid, the solution saturated with hydrogen chloride and heated in a sealed tube at 150°C for 2 hours. The dark reaction mixture was concentrated to dryness in vacuo, excess acid removed by flushing several times with ethanol. On dissolving the dark residue in a minimum amount of water and adjusting the clarified solution to pH 6.5 with ammonium hydroxide the compound separated in fine crystals which were filtered, washed with alcohol and ether. The crystalline product had a MP of 299.5 to 300°C with decomposition.
Then, as described in US Patent 3,158,648, the optical isomers may be resolved as follows. 37 g of racemic α-methyl-3,4-dihydroxyphenylalanine are slurried at 35°C in 100 cc of 1.0 N hydrochloric acid. The excess solids are filtered leaving a saturated solution containing 34.6 g of racemic amino acid of which about 61% is present as the hydrochloride. The solution is then seeded at 35°C with 7 g of hydrated L-α-methyl-3,4-dihydroxyphenylalanine (6.2 g of anhydrous material). The mixture is then cooled to 20°C in 30 minutes and aged one hour at 20°C. The separated material is isolated by filtration, washed twice with 10 cc of cold water and dried in vacuo. The yield of product is 14.1 g of L-α-methyl-3,4-dihydroxyphenylalanine in the form of a sesquihydrate of 100% purity as determined by the rotation of the copper complex.

Therapeutic Function

Antihypertensive

Biological Functions

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.

General Description

Colorless or almost colorless crystals or white to yellowish-white fine powder. Almost tasteless. In the sesquihydrate form. pH (saturated aqueous solution) about 5.0.

General Description

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.

Air & Water Reactions

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).

Reactivity Profile

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

Fire Hazard

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

Biological Activity

L-aromatic amino acid decarboxylase inhibitor. Antihypertensive.

Mechanism of action

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.

Pharmacokinetics

Antihypertensive effects of methyldopa are mostly mediated by its pharmacologically active metabolite, alpha-methylnorepinephrine, which works as an agonist at central inhibitory alpha-adrenergic receptors. Stimulation of alpha-adrenergic receptors leads to decreased peripheral sympathetic tone and reduced arterial pressure. Methyldopa causes a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine. Overall, methyldopa lowers both standing blood pressure and especially supine blood pressure, with infrequent symptomatic postural hypotension. Methyldopa also reduces plasma renin activity but has negligible effects on glomerular filtration rate, renal blood flow, or filtration fraction. It also has no direct effect on cardiac function but in some patients, a slowed heart rate may occur.
Following oral administration, blood-pressure-lowering effects are observed within 12 to 24 hours in most patients, and a maximum reduction in blood pressure occurs in 4 to 6 hours. Blood pressure returns to pre-treatment levels within 24 to 48 hours following drug discontinuation. Following intravenous administration, the blood-pressure-lowering effects of methyldopa last for about 10 to 16 hours.

Pharmacology

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.

Pharmacokinetics

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.

Clinical Use

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.

Side Effects

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.

Safety Profile

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

Synthesis

Methyldopa, (-)-3-(3,4-dihydroxyphenyl)-2-methylalanine (22.2.5), is synthesized by a few methods that are only slightly different. The first method is from 3,4- dimethoxyphenylacetone, which undergoes a Strecker¨CZelinski reaction using potassium cyanide and ammonium carbonate, to give 4-methyl-4-(3,4-dimethoxybenzylhydantoine (22.3.3), which is further hydrolyzed in the presence of barium hydroxide to give (
)-3-(3,4-dimethoxyphenyl)-2-methylalanine (22.3.4). This undergoes acetylation at the amino group, and the racemic mixture is then separated using (-)-1-phenylethylamine. The isolated isomer is hydrolyzed using hydrobromic acid, which simultaneously removes the methoxy- and acetyl groups to give the desired (-)-3-(3,4-dihydroxyphenyl)-2-methylalanine (22.3.5) [8¨C10]. Alternative syntheses have been proposed.

Drug interactions

Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Antidepressants: avoid concomitant use with MAOIs.
Lithium: neurotoxicity (without increased plasma lithium concentrations).
Salbutamol: acute hypotension reported with
salbutamol infusions.

Metabolism

Two isomers of methyldopa undergo different metabolic pathways. L-α-methyldopa is biotransformed to its pharmacologically active metabolite, alpha-methylnorepinephrine. Methyldopa is extensively metabolized in the liver to form the main circulating metabolite in the plasma, alpha (α)-methyldopa mono-O-sulfate. Its other metabolites also include 3-O-methyl-α-methyldopa; 3,4-dihydroxyphenylacetone; α-methyldopamine; and 3-O-methyl-α-methyldopamine. These metabolites are further conjugated in the liver to form sulfate conjugates. After intravenous administration, the most prominent metabolites are alpha-methyldopamine and the glucuronide of dihydroxyphenylacetone, along with other uncharacterized metabolites.
D-α-methyldopa, which is the inactive isomer of methyldopa, is also metabolized to 3-O-methyl-α-methyldopa and 3,4-dihydroxyphenylacetone to a minimal extent; however, there are no amines (α-methyldopamine and 3-O-methyl-α-methyldopamine) formed.

Metabolism

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.

storage

Room temperature

Purification Methods

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.]