Methyldopa

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Antihypertensives

Minute, anhyd crystals from methanol

WHITE TO YELLOWISH WHITE, FINE POWDER, WHICH MAY CONTAIN FRIABLE LUMPS

1 to 10 mg/mL at 73 °F (NTP, 1992)

Sol in water @ 25 °C: approx 10 mg/ml /D-form/

Sol in water @ 25 °C: approx 18 mg/ml /DL-form/

In water @ 25 °C: about 10 mg/ml; practically insol in common org solvents; sol in dil mineral acids

Soluble in isopropanol, ethanol, and water.

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Adrenergic alpha-2 Receptor Agonists

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Antihypertensive medicines

572 °F approximately (decomposes) (NTP, 1992)

>300

300 °C

This chemical does not meet GHS hazard criteria for 50% (1 of 2) of reports.

Warning

H361 (50%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 2 reports by companies from 2 notifications to the ECHA C&L Inventory.

SYMPTOMS: Symptoms of exposure to this compound include edema (fluid retention), fever, diarrhea, mental depression, hepatic toxicity, arthralgia (with or without joint swelling), leukopenia, breast enlargement, amenorrhea, pancreatitis, myocarditis and hemolytic anemia. Parkinsonism, hypertension and galactorrhea (lactation) may occur. Reversible keratitis may also occur. Other symptoms include sedation (usually transient), asthenia, congestive heart failure, weight gain, vomiting, sialadenitis, sore or "black" tongue, distention, flatus, hyperprolactinemia, bone marrow depression, rheumatoid factor, abnormal liver function tests, pericarditis, decreased mental acuity, symptoms of cerebrovascular insufficiency, psychic disturbances including nightmares and reversible mild psychoses, rise in BUN, toxic epidermal necrosis and decreased libido. Exposure can cause headache, weakness, aggravation of angina pectoris, prolonged carotid sinus hypersensitivity, postural hypotension, bradycardia, colitis, nausea, constipation, dryness of the mouth, granulocytopenia, thrombocytopenia, positive tests for antinuclear antibody, LE cells, positive Coombs test, liver disorders including hepatitis and jaundice, lupus-like syndrome, Bell's palsy, involuntary choreoathetotic movements, dizziness, lightheadedness, paresthesias, myalgia, nasal stuffiness, skin rash and impotence. Exposure can also cause drowsiness, gastrointestinal upset, disorders of sexual function, salivary gland inflammation, uremia, liver damage (including cirrhosis), darkened urine, eosinophilia, syncope, cholestasis, eczema, oral ulceration, hyperpyrexia, ocular disturbances, febrile reaction, joint pain, nodular skin lesions, retroperitoneal fibrosis and biliary carcinoma. There has been a case of reversible malabsorption with partial villous atrophy, inflammatory infiltrate of the mucosa and giant-cell granuloma. Other symptoms may include sleep disturbances, anxiety, blurred vision, hepatic necrosis and lichenoid and granulomatous skin reactions. It may also cause menstrual cycle changes or disorders and effects on the newborn including abnormal neonatal measures, growth statistics and biochemical and metabolic changes.

Asthma reported in the pharmaceutical industry; [Malo] As an oral medication, methyldopa is used to treat hypertension. Many side effects have been reported after ingestion of therapeutic doses, including immune hemolytic anemia and drug-induced hepatitis. [HSDB]

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

DHHS/NTP; Toxicology & Carcinogenesis Studies of alpha-Methyldopa Sesquihydrate in F344/N Rats and B6C3F1 Mice Technical Report Series No. 348 (1989) NIH Publication No. 89-2803 /alpha-Methyldopa sesquihydrate/

MCLEOD PJ; ALPHA-METHYLDOPA INT SYMP 29 (1981) A REVIEW ON THE PHARMACOKINETICS OF ALPHA-METHYLDOPA.

KERSTING F ET AL; CLIN EXP PHARMACOL PHYSIOL, SUPPL, 4(ISS MECH ACTIONS ALPHA-METHYLDOPA ANTIHYPERTENS TREAT) 11 (1978) REVIEW ON SITE OF ACTION OF ALPHA-METHYLDOPA IN LOWERING BLOOD PRESSURE.

BOUDIER HA J ET AL; ALPHA-METHYLDOPA INT SYMP 35 (1981) A REVIEW WITH 37 REF ON THE HEMODYNAMIC EFFECT OF ALPHA-METHYLDOPA IN HYPERTENSION AND THE ROLE OF THE SYMPATHETIC NERVOUS SYSTEM IN THE MECHANISM OF ACTION.

A REVIEW ON METHYLDOPA IN THE TREATMENT OF HYPERTENSION.[SJOERDSMA A; METHYLDOPA; BR J CLIN PHARMACOL 13(1) 45 (1982)]

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).

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. If symptoms (such as redness or irritation) develop, immediately transport the victim to a hospital.

Methyldopa oral suspension should be stored in tight, light-resistant containers at a temperature less than 26 °C and protected from freezing. Methyldopa tablets should be stored in well-closed containers at a temperature less than 40 °C, preferably at 15-30 °C.

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

In the event of overdosage, symptomatic and supportive measures should be employed. When ingestion is recent, gastric lavage or emesis may reduce absorption. When ingestion has been earlier, infusions may be helpful to promote urinary excretion. Otherwise, management includes special attention to cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity (A308).

LEVODOPA...REPORTED TO AUGMENT ANTIHYPERTENSIVE EFFECT OF METHYLDOPA IN MAN.

ACUTE HYPOTENSIVE EFFECT OF METHYLDOPA HAS BEEN REPORTED TO BE ABOLISHED BY PRETREATMENT WITH RESERPINE, IMIPRAMINE, & INTRAVENTRICULAR 6-HYDROXYDOPAMINE, & TO BE ENHANCED BY MONOAMINE OXIDASE INHIBITOR TRANYLCYPROMINE. HYPOTENSION...BLOCKED BY INTRAVENTRICULAR ADMIN OF SMALL DOSE OF PHENTOLAMINE...

METHYLDOPA...REPORTED TO AUGMENT AMPHETAMINE-INDUCED HYPERACTIVITY IN MICE...

PHENOBARBITAL REPORTEDLY MAY INDUCE METABOLISM OF METHYLDOPA WHEN THESE AGENTS ARE ADMIN CONCURRENTLY. ... RELATED DRUGS--OTHER BARBITURATES WOULD BE EXPECTED TO ACT SIMILARLY TO PHENOBARBITAL.

For more Interactions (Complete) data for METHYLDOPA (18 total), please visit the HSDB record page.

Drug induced liver injury due to methyldopa was identified shortly after its introduction into medical use in the 1960’s. Chronic use of methyldopa is associated with mild and transient elevations in serum aminotransferase levels in 5% to 35% of patients, these elevations often resolving despite continuation of the medication. In contrast, clinically apparent or significant liver injury from methyldopa is relatively uncommon, although several hundred cases have been reported. Two patterns of hepatotoxicity have been described: an acute hepatitis that appears within weeks to months of starting treatment, and a chronic hepatitis that arises months to years after initiation of methyldopa therapy.

Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.

Common adverse effects include:

Methyldopa is distributed into milk; peak milk concentrations of free methyldopa are approximately 20-35% of those in maternal plasma following an individual dose during continuous therapy. The extent of distribution of methyldopa into milk has not been clearly determined, but it is estimated that about 0.02% of a daily maternal dose of 1 g would be ingested by a nursing infant and that this amount is probably not clincially important.

IDENTIFICATION: Methyldopa is a colorless or almost colorless crystal or a white to yellowish-white fine powder which may contain friable lumps. Slightly soluble in water and alcohol; practically insoluble in chloroform and ether; dissolves in dilute mineral acids. Practically insoluble in the common organic solvents. Indications: Treatment of moderate to severe hypertension usually in combination with diuretic or a beta-blocking agent. Methyldopa has been used in the treatment of severe dyskinesias. HUMAN EXPOSURE: Main risks and target organs: Acute overdose: the target organs are the central nervous system and the cardiovascular system. The main risks are hypotension, bradycardia, cardiac arrhythmia and hypothermia. Chronic poisoning and adverse effects: the target organs are the central nervous system, cardiovascular system, liver, pancreas and immunological system. Acute: drowsiness, coma, hypotension, bradycardia, dry mouth, impairment of atrioventricular conduction, and hypothermia. Chronic: CNS manifestations: sedation, parkinsonism, choreoathetoid movements, headache and vertigo. Cardiovascular effects: bradycardia, prolonged carotid sinus hypersensitivity, myocarditis, pericarditis, aggravation of angina pectoris, postural hypotension, first-degree heart block. Gastrointestinal effects diarrahea, colitis, dryness of the mouth, black tougue, reversible malabsorption, pancreatitis. Liver disorders: hepatitis. Hypersensitivity reactions: rash, urticaria, eczema, lichenoid eruptions. Hematological manifestations : positive Coomb's test, leucopenia, hemolysis. Contraindications: Active hepatic disease, such as acute hepatitis and active cirrhosis.Methyldopa is not recommended for patients with pheochromocytoma. Rarely, involuntary choreoathetoid movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease should avoid methyldopa. Older patients with advanced arteriosclerotic disease should be given lower dose of methyldopa to avoid syncope. Methydopa should be used with caution in patients with impaired kidney function or mental depression. Methydopa has been reported to aggravate porphyria. Oral : Intentional ingestion of large doses may occur. When administered orally, methyldopa is absorbed by an active amino acid transport. Methyldopa is incompletely and variably absorbed from the gastrointestinal tract. Oral bioavailability is variable (50%). Peak concentrations in plasma occur after 2 to 3 hours. Plasma level of methyldopa does not correlate with its clinical effect. Methyldopa crosses the placenta. Methyldopa crosses the blood brain barrier. The transport of methyldopa into CNS is apparently an active process. Methyldopa is partly conjugated, mainly to the methyldopa-O-sulfate. The major metabolite probably contributes little to the therapeutic effect except in patients with renal failure. Other metabolites include methyldopamine, methylnorepinephrine, and O-methylated compounds. Methyldopa is excreted by the kidneys. Elimination is phasic. 95% of the drug is eliminated in the initial phase with a half-life of 0.21 hour. In the second phase, the limitation half-life averages 1.28 hours. Twenty-five percent of unchanged methyldopa is excreted in the urine within 24 hours. Methyldopa reduces vascular resistance. The fall in arterial pressure is maximal 6 to 8 hours after an oral. Hypotension can be increased by concurrent administration of diuretics and other antihypertensive agents, and general anesthetics. Concomittant use of methyldopa and digoxin may produce symptomatic sinus bradycardia. Concomitant use of metyldopa and lithium carbonate appeared to induce signs of lithium toxicity.The action of methyldopa may be decreased by simultaneous use of non-steroidal anti-inflamatory agents. CNS depressants including alcohol and narcotic analgesics, may potentiate the hypotensive action of methyldopa to a dangerous degree. When methyldopa is administered with sedatives, hypnotics, tranquilizers, or other central nervous system depressants, further central nervous system depression may occur. The hypotensive action of methyldopa may be inhibited by amphetamines and other sympathomimetic drugs, monoamine oxidase inhibitors, and tricyclic antidepressants. Methyldopa may increase the hypoglycemic effects of tolbutamide. Methyldopa may increase prothrombin time if added to treatment with anticoagulants. Methyldopa may decrease the effect of ephedrine, since it reduces the quantity of norepinephrine in sympathetic nerve endings. Methyldopa used with haloperidol and chlorpromazine may produce psychomotor retardation, memory impairment, and inability to concentrate. Methyldopa used with monoamine oxidase inhibitor drugs may produce headache and hypertension. Sedation, headache, asthenia, drowsiness, depression, impaired mental acuity, impaired ability to concentrate, lapses of memory, nightmares, nausea, dryness of the mouth, nasal stuffiness, dizziness, vertigo, edema, disorders of sexual function, weight gain, orthostatic hypotension with lightheadedness. Breast enlargement, lactation, hyperprolactinemia, black or sore tongue, salivary gland inflammation, pancreatitis, paresthesias, Bell's palsy, parkinsonism, diarrhea, constipation, fever, arthralgia, myalgia, uremia, myocarditis, aggravation of angina pectoris, bradycardia, atrioventricular conduction disturbances. A paradoxical pressor response is seen after intravenous methyldopate hydrochloride. Rebound hypertension has been reported after abrupt withdrawal of oral administration. Thrombocytopenia, Leucopenia, granulocytopenia, hemolytic anemia have been reported along with fever, jaundice and liver damage. Systemic lupus erythematosus like syndrome, rash, urticarria, eczema and hyperkeratosis. Infrequent CNS effects include reversible mild psychosis, depression blurred vision.

Methyldopa overdose reports are exceedingly rare. Clinical manifestations include coma, hypothermia, hypotension, bradycardia, and dry mouth. In addition, prolonged, severe hypotension, along with marked renal potassium loss necessitating IV infusion of norepinephrine and vigorous potassium replacement therapy for almost two days, was reported.

Although the mechanism of action has yet to be conclusively demonstrated, the resultant hypotensive effect is most likely due to the drug's action on the CNS. Methyldopa is converted into the metabolite, alpha-methylnorepinephrine, in the CNS, where it stimulates the central inhibitory alpha-adrenergic receptors, leading to a reduction in sympathetic tone, total peripheral resistance, and blood pressure. Reduction in plasma renin activity, as well as the inhibition of both central and peripheral norepinephrine and serotonine production may also contribute to the drug's antihypertensive effect, although this is not a major mechanism of action. This is done through the inhibition of the decarboxylation of dihydroxyphenylalanine (dopa) - the precursor of norepinephrine - and of 5-hydroxytryptophan (5-HTP) - the precursor of serotonin - in the CNS and in most peripheral tissues.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. /Methyldopa sesquihydrate/ [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=41372-08-1]

...ADVERSE REACTIONS INCL DRUG FEVER &, RARELY, GRANULOCYTOPENIA & THROMBOCYTOPENIA.

SALT & WATER OFTEN ARE GRADUALLY RETAINED WITH PROLONGED USE OF METHYLDOPA ...

... METHYLDOPA PRODUCES SEDATION THAT IS LARGELY TRANSIENT.

A diminution in psychic energy may be a persistent effect in some patients, and depression occurs occasionally. ... Methyldopa may produce dryness of the mouth. Other side effects that are related to the pharmacological effects in the CNS include ... parkinsonian signs, and hyperprolactinemia that may become sufficiently pronounced to cause gynecomastia and galactorrhea.

For more Human Toxicity Excerpts (Complete) data for METHYLDOPA (13 total), please visit the HSDB record page.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

C - Cardiovascular system

QC - Cardiovascular system

C02AB01

Methyldopa is less than 15% bound to plasma proteins and its primary metabolite, O-sulfate metabolite, is about 50% protein bound. Following intravenous administration, approximately 17% of the dose in normal subjects were circulating in the plasma as free methyldopa.

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.

The exact mechanism of methyldopa is not fully elucidated; however, the main mechanisms of methyldopa involve its actions on alpha-adrenergic receptor and the aromatic L-amino acid decarboxylase enzyme, to a lesser extent. The sympathetic outflow is regulated by alpha (α)-2 adrenergic receptors and imidazoline receptors expressed on adrenergic neurons within the rostral ventrolateral medulla. Methyldopa is metabolized to α‐methylnorepinephrine via dopamine beta-hydroxylase activity and, consequently, alpha-methylepinephrine via phenylethanolamine-N-methyltransferase activity. Mediating the therapeutic effects of methyldopa, α‐methylnorepinephrine and α-methylepinephrine active metabolites are agonists at presynaptic alpha-2 adrenergic receptors in the brainstem. Stimulating alpha-2 adrenergic receptors results in the inhibition of adrenergic neuronal outflow and attenuation of norepinephrine release in the brainstem. Consequently, the output of vasoconstrictor adrenergic signals to the peripheral sympathetic nervous system is reduced, leading to a reduction in blood pressure. The L-isomer of alpha-methyldopa also reduces blood pressure by inhibiting aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase, which is an enzyme responsible for the syntheses of dopamine and serotonin. Inhibiting this enzyme leads to depletion of biogenic amines such as norepinephrine. However, inhibition of aromatic L-amino acid decarboxylase plays a minimal role in the blood-pressure‐lowering effect of methyldopa.

METHYLDOPA...HAS HYPOTENSIVE ACTION INDEPENDENT OF ITS ANTIADRENERGIC ACTIONS; THIS IS PROBABLY PARTLY CENTRAL DEPRESSANT ACTION @ VASOMOTOR CENTER & PARTLY PERIPHERAL ACTION OF UNKNOWN MECHANISM.

... Alpha-methylnorepinephrine acts in the brain to inhibit adrenergic neuronal outflow from the brainstem, and this central effect is principally responsible for its antihypertensive action.

IN CONSCIOUS RENAL HYPERTENSIVE RATS ALPHA-METHYLDOPA PRODUCED A LONG-LASTING FALL IN BLOOD PRESSURE WHICH WAS PARTIALLY ATTENUATED BY PRETREATMENT WITH NALTREXONE (5 MG/KG SC). PRETREATMENT WITH ANTISERUM TO BETA-ENDORPHIN APPLIED LOCALLY, ALSO BLOCKED THE DEPRESSOR RESPONSE. THESE RESULTS SUGGEST THAT THE FALL IN BLOOD PRESSURE OBSERVED AFTER ALPHA-METHYLDOPA AND ITS ACTIVE METABOLITE ALPHA-METHYLNORADRENALINE INVOLVES A BETA-ENDORPHIN LIKE PEPTIDE; A POSSIBLE SITE OF ACTION IS THE NUCLEUS TRACTUS SOLITARII.

A REVIEW ON THE MECHANISM OF ACTION.

The plasma half-life of methyldopa is 105 minutes. Following intravenous injection, the plasma half-life of methyldopa ranges from 90 to 127 minutes.

The drug is ... eliminated with a half-life of about 2 hr. ... The half-life of methyldopa is prolonged to 4-6 hr in patients with renal failure.

DISAPPEARANCE OF THE DRUG FROM PLASMA AFTER IV ADMIN IS BIPHASIC, & THE TERMINAL HALF-TIME OF ELIMINATION FROM PLASMA IS ABOUT 2 HOURS. RENAL EXCRETION ACCOUNTS FOR ABOUT TWO THIRDS OF THE CLEARANCE OF DRUG FROM PLASMA.

IN PT WITH SEVERELY IMPAIRED RENAL FUNCTION, ONLY ABOUT 50% OF DRUG IS EXCRETED DURING EARLY PHASE (T/2= 3 1/2 HR), & SOME ACCUMULATION CAN OCCUR DURING CHRONIC ADMIN... BOTH TOTAL QUANTITY ABSORBED & DISTRIBUTION OF METABOLITES IN URINE CAN VARY CONSIDERABLY IN DIFFERENT INDIVIDUALS & IN SAME PT FROM DAY TO DAY.

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.

METHYLDOPA YIELDS 3,4-DIHYDROXY-ALPHA-METHYLPHENETHYLAMINE, 3,4-DIHYDROXY-ALPHA-METHYL-L-PHENYLALANINE-O-SULFATE, & 4-HYDROXY-3-METHOXY-ALPHA-METHYL-L-PHENYLALANINE IN MAN. /FROM TABLE/

METHYLDOPA...UNDERGOES DECARBOXYLATION & BETA-HYDROXYLATION IN MOUSE & RABBIT BRAIN TO YIELD ALPHA-METHYLNORADRENALINE.

...ADMIN IP TO RATS (14)C-METHYLDOPA IS EXCRETED IN URINE AS...3-O-METHYL-METHYLDOPA (14%), METHYLDOPAMINE & ITS CONJUGATES (2%), 3-O-METHYL-METHYLDOPAMINE & ITS CONJUGATES (6%), 3-METHOXY-4-HYDROXYPHENYLACETONE (6%), & 3,4-DIHYDROXYPHENYLACETONE (10%).

A REVIEW ON THE METAB OF ALPHA-METHYLDOPA.

Hepatic, extensively metabolized. The known urinary metabolites are: a-methyldopa mono-0-sulfate; 3-0-methyl-a-methyldopa; 3,4-dihydroxyphenylacetone; a-methyldopamine; 3-0-methyl-a-methyldopamine and their conjugates. Route of Elimination: Methyldopa is extensively metabolized. The known urinary metabolites are: alpha-methyldopa mono-O-sulfate; 3-0-methyl-alpha-methyldopa; 3,4-dihydroxyphenylacetone; alpha-methyldopamine; 3-0-methyl-alpha-methyldopamine and their conjugates. Approximately 70 percent of the drug which is absorbed is excreted in the urine as methyldopa and its mono-O-sulfate conjugate. Methyldopa crosses the placental barrier, appears in cord blood, and appears in breast milk. Half Life: The plasma half-life of methyldopa is 105 minutes.

M4R0H12F6M

METHYLDOPA ANHYDROUS

Mechanisms of Action [MoA] - Adrenergic alpha2-Agonists

Established Pharmacologic Class [EPC] - Central alpha-2 Adrenergic Agonist

Methyldopa anhydrous is a Central alpha-2 Adrenergic Agonist. The mechanism of action of methyldopa anhydrous is as an Adrenergic alpha2-Agonist.

METHYLDOPA

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

Drugs that inhibit the actions of the sympathetic nervous system by any mechanism. The most common of these are the ADRENERGIC ANTAGONISTS and drugs that deplete norepinephrine or reduce the release of transmitters from adrenergic postganglionic terminals (see ADRENERGIC AGENTS). Drugs that act in the central nervous system to reduce sympathetic activity (e.g., centrally acting alpha-2 adrenergic agonists, see ADRENERGIC ALPHA-AGONISTS) are included here.

Compounds that bind to and activate ADRENERGIC ALPHA-2 RECEPTORS.

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.

Approximately 70% of absorbed methyldopa is excreted in the urine as unchanged parent drug (24%) and α-methyldopa mono-O-sulfate (64%), with variability.3-O-methyl-α-methyldopa accounted for about 4% of urinary excretion products. Other metabolites like 3,4-dihydroxyphenylacetone, α-methyldopamine, and 3-O-methyl-α-methyldopamine are also excreted in urine. Unabsorbed drug is excreted in feces as the unchanged parent compound. After oral doses, excretion is essentially complete in 36 hours. Due to attenuated excretion in patients with renal failure, accumulation of the drug and its metabolites may occur, possibly leading to more profound and prolonged hypotensive effects in these patients.

The apparent volume of distribution ranges between 0.19 and 0.32L/kg and the total volume of distribution ranges from 0.41 to 0.72L/kg. Since methyldopa is lipid-soluble, it crosses the placental barrier, appears in cord blood, and appears in breast milk.

The renal clearance is about 130 mL/min in normal subjects and is decreased in patients with renal insufficiency.

(14)C-METHYLDOPA ADMIN ORALLY TO HYPERTENSIVE PT IS RECOVERED EQUALLY FROM URINE & FECES; PRODUCT IN FECES IS UNCHANGED METHYLDOPA, & IN URINE METHYLDOPA & ITS ETHEREAL SULFATE, TOGETHER WITH SMALL AMT OF 3-O-METHYL-METHYLDOPA & METHYLDOPAMINE.

METHYLDOPA CROSSES THE PLACENTA...

MEDICATION

ANTIHYPERTENSIVE AGENT

Use (kg; approx.) in Germany (2009): >2500

For use in the treatment of hypertension (A308).

(1975) 6.8X10+3 GRAMS (PRINCPL CUSTMS DISTS)

(1983) 3.15X10+5 g

(1972) PROBABLY GREATER THAN 4.54X10+5 GRAMS

(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS

Pfister, Stein, US patent 2,868,818 (1959 to Merck & Co). Resolution: Jones et al, US patent 3,158,648 (1964 to Merck & Co); Compare Slates et al, J Org Chem 29, 1424 (1964). ... Synth from asymmetric intermediates: Reinhold et al, J Org Chem 33, 1209 (1968).

The product of the reaction of 3,4-dimethoxyphenylacetonitrile with sodium ethoxide is hydrolyzed with acid to give 3,4-dimethoxyphenylacetone. This is reacted with ammonium carbonate and potassium cyanide to form a substituted hydantoin intermediate which, on alkaline hydrolysis, yields racemic methyldopa. The acetylated form of this racemate is resolved using (-)-alpha-methylbenzylamine. The isolated acetylated (-)-methyldopate salt is deacetylated with base and treated with mineral acid to liberate (-)-methyldopa. US Pat 2,868,818