| GHS-Einstufung | This chemical does not meet GHS hazard criteria for 50% (1 of 2) of reports.WarningH361 (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. |
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| Regulatorische Informationen | Methyldopa: Does not have an individual approval but may be used under an appropriate group standard |
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| Weitere Sicherheitsinformationen | IMAP assessments - L-Tyrosine, 3-hydroxy-.alpha.-methyl-: Environment tier I assessment |
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| Brandgefahren | Flash point data for this chemical are not availablehowever, it is probably combustible. (NTP, 1992) |
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| Gesundheitsgefahren | 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. |
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| Gefahrenübersicht | 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] |
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| FDA-Anforderungen | 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 amended21 U.S.C. 321-392). |
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| Reaktive Gruppe | Acids, Carboxylic |
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| Special Reports | DHHS/NTPToxicology & 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 PJALPHA-METHYLDOPA INT SYMP 29 (1981) A REVIEW ON THE PHARMACOKINETICS OF ALPHA-METHYLDOPA.KERSTING F ET ALCLIN 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 ALALPHA-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 ABR J CLIN PHARMACOL 13(1) 45 (1982)] |
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| Reactivity Profile | METHYL DOPA undergoes catalytic oxygenation in the presence of magnesium, cupric, cobalt, nickel and ferric ions (NTP, 1992). A weakly acidic amino acid. |
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| Air and 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). |
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| Hazard Classes and Categories | Repr. 2 (50%) |
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| Brandbekämpfung | Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992) |
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| Erste Hilfe | 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. |
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| Lagerbedingungen | 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. |
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| Freisetung ohne Brand | 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. |
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| Entsorgungsverfahren | 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. |
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| Personal Protective Equipment (PPE) | 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) |
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| Treatment | 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). |
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| Wechselwirkungen | 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. |
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| Gesundheitliche Auswirkungen | Acute overdosage may produce acute hypotension with other responses attributable to brain and gastrointestinal malfunction. Haemolytic anaemia, bone marrow suppression, and parkinsonism may also occur (RxList A308, L1178). |
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| Hepatotoxicity | 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. |
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| Unerwünschte Wirkungen | 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: |
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| Expositionspfade | Oral (A308). Absorption from the gastrointestinal tract is variable but averages approximately 50%. |
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| Milk Concentrations | Methyldopa is distributed into milkpeak 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. |
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| Toxizitätsübersicht | 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 alcoholpractically insoluble in chloroform and etherdissolves 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. |
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| Signs and Symptoms | Excessive sedation, weakness, bradycardia, dizziness, lightheadedness, bloating, constipation, distention, flatus, diarrhea, nausea, vomiting and severely low blood pressure (RxList A308). |
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| Ongoing Test Status | 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] |
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| Human Toxicity Excerpts | ...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. |
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| Carcinogen Classification | No indication of carcinogenicity to humans (not listed by IARC). |
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| F | 10-23 |
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| Wassergefährdungsklasse (WGK) | 3 |
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| Zollcode | 2922504500 |
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| RTECS-Nr. | YP2860000 |
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| R-Sätze (R) | 20/21-36/37/38-42/43-65 |
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| Sicherheitshinweise (S) | 24/25 |
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| Lagerklasse | 11 - Combustible Solids |
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