Methyldopa

211.21

211.21

209-089-2

M4R0H12F6M

760080

DTXSID5020863|DTXSID5023295

Minute, anhyd crystals from methanol|WHITE TO YELLOWISH WHITE, FINE POWDER, WHICH MAY CONTAIN FRIABLE LUMPS

C - Cardiovascular system

2918199090

104

-1.79

Methyl dopa appears as 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. (NTP, 1992)

1.4±0.1 g/cm3

300 °C (decomp)

441.6±45.0 °C at 760 mmHg

220.9±28.7 °C

1.635

H2O: 10g/L(temperature not stated)

Store at RT

LD50 oral in rabbit: 713mg/kg

Max absorption: 281 nm (e= 2780); Specific optical rotation (1 in 0.1 N HCl): -4.0 +/- 0.5 deg @ 23 °C/D

ODORLESS

ALMOST TASTELESS

pH of saturated aq soln about 5.0

147.6 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]|146.8 Ų [M+Na]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Considerably hygroscopic; decomp @ approx 300 °C; exists as sesquihydrate|Crystals from water /sesquihydrate/

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).

Acids, Carboxylic

METHYL DOPA undergoes catalytic oxygenation in the presence of magnesium, cupric, cobalt, nickel and ferric ions (NTP, 1992). A weakly acidic amino acid.

3

S24/25

YP2860000

Methyldopa is decomposed by oxidizing agents.

P261, P264, P270, P271, P273, P280, P301+P312, P302+P352, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, P501

H302

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.

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)]

Flash point data for this chemical are not available; however, it is probably combustible. (NTP, 1992)

|Warning|H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]|P201, P202, P281, P308+P313, P405, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory.|Danger|H302 (40%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P261, P264, P270, P271, P273, P280, P281, P301+P312, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P314, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 5 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

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. STORAGE PRECAUTIONS: You should keep this material in a tightly closed container under an inert atmosphere, and store it at refrigerated temperatures. (NTP, 1992)

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)

The oral LD50 of methyldopa is greater than 1.5 g/kg in both the mouse and the rat. Symptoms of overdose include bloating, constipation, diarrhea, dizziness, extreme drowsiness, gas, light-headedness, nausea, severely low blood pressure, slow heartbeat, vomiting, and weakness.|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.

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.

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.

LD50 Rat oral 5000 mg/kg|LD50 Rat ip 300 mg/kg|LD50 Mouse ip 150 mg/kg|LD50 Mouse iv 1700 mg/kg|For more Non-Human Toxicity Values (Complete) data for METHYLDOPA (6 total), please visit the HSDB record page.

alpha-Methyldopa sesquihydrate (USP grade, greater than 99% pure) was selected for study because of widespread human exposure and the lack of carcinogenicity studies on this cmpd. ... Two yr studies were conducted in F344/N rats and B6C3F1 mice. The chemical was admin in feed because human exposure is primarily by the oral route. ... Dietary concn selected for male and female rats in the 2 yr studies were 0, 3,100, and 6,300 ppm. ... Dietary concn selected for male and female mice in the 2 yr studies were 0, 6,300, and 12,500 ppm. Diets containing the chemical at these concn were fed to groups of 50 male and 50 female rats and 50 male and 50 female mice for 103 wk. Conclusions: Under the conditions of these 2 yr feed studies, there was no evidence of carcinogenic activity of alpha-methyldopa sesquihydrate for male or female F344/N rats fed diets containing 3,100 or 6,300 ppm. There was equivocal evidence of carcinogenic activity of alpha-methyldopa sesquihydrate for male B6C3F1 mice, as shown by three dosed mice having uncommon tubular cell tumors of the kidney. There was no evidence of carcinogenic activity of alpha-methyldopa sesquihydrate for female B6C3F1 mice fed diets containing 6,300 or 12,500 ppm. ...|Alpha-Methyldopa (MD) ... was evaluated for toxic & teratogenic effects in timed-pregnant CD rats exposed to alpha-Methyldopa on gestational days (gd) 6-20 & sacrificed on gestational day 20. Prior to the initiation of the teratology study, a preliminary study was conducted in order to establish appropriate doses for use in the teratology study. In the preliminary dose range-finding study, alpha-methyldopa, suspended in corn oil, was administered by gavage to timed-pregnant CD rats at doses of 0, 100, 250, 500, 750, & 1,000 mg/kg/day (6 animals/group) on gestational days 6-20. Animals were sacrificed & evaluated on gestational day 20. The results of the preliminary dose range-finding study indicated that the 1,000 mg/kg/day dose caused 33% mortality of confirmed-pregnant dams, & was therefore unsuitable for use in the teratology study. A probit plot analysis of the mortality data from the preliminary study suggested an LD10 of 581 mg/kg/day. Accordingly, doses of 0, 50, 100, 250, & 500 mg/kg/day alpha-methyldopa were chosen for admin in the teratology study. In the teratology study, alpha-methyldopa suspended in corn oil (0, 50, 100, 250 & 500 mg/kg/day) was administered by gavage to timed-pregnant CD rats on gestational days 6-20. The study was conducted using a two-replicate design, with 10-20 animals assigned to each dose group in each replicate. In each replicate, females were weighed & observed during daily treatment for clinical signs of toxicity. At sacrifice on gestational day 20, the gravid uterus of each dam was weighed. Following uterine dissection the number & status of uterine implantation sites was recorded. Each live fetus was weighed, sexed, & examined for external, visceral, & skeletal malformations. Fetal heart, whole head, & liver weight were recorded. A total of 19-22 dams (i.e., confirmed-pregnant females)/treatment group were evaluated in the study. During alpha-methyldopa treatment, dams in the teratology study exhibited observable signs of toxicity including lethargy, chromodacryorrhea, blue discoloration of the nose, diarrhea, rough coat, vaginal bleeding, & urogenital staining & wetness. Clinical signs of toxicity were observed most frequently at doses of 100 mg/kg/day or more. The maternal mortality was 0%, 0%, 0%, 8.7%, & 34.5% for animals in the vehicle through high dose group, respectively. The unexpected high mortality in the 500 mg/kg/day dose group was observed predominantly in the first replicate; exam of the study records did not provide an explanation for this occurrence. MD at doses of 100 mg/kg/day or more significantly reduced maternal body weight, maternal weight gain, gravid uterine weight & absolute maternal liver weight. Alpha-methyldopa significantly increased embryotoxicity at the 500 mg/kg/day dose level, as evidenced by a significant incr in the % resorptions/litter, the % nonlive implants/litter (resorptions & dead fetuses) & the % adversely affected implants/litter (nonlive implants plus malformed live fetuses). A trend toward an incr in the % dead fetuses/litter, % litters with dead fetuses, % litters with nonlive implants, & % litters with adversely affected implants was observed. However, this trend was not strictly dose-related & was determined primarily by an incr in these parameters at the high dose. For litters with live fetuses, the number of live fetuses/litter exhibited a trend toward a decr that did not appear to be biologically significant. However, avg fetal body weight/litter (male, female, or sexes combined) decreased as the dose of MD increased, with the 100, 250, & 500 mg/kg/day dose groups significantly below controls. The % fetuses malformed/litter & % male fetuses malformed/litter exhibited a trend toward an incr that was determined primarily by marginal increases occurring in the 250 & 500 mg/kg/day dose groups. This trend was not observed for the % female fetuses malformed/litter. Alpha-methyldopa was not associated with any specific malformation or group of malformations. For gestational day 20 rat fetuses, relative female fetal heart weight/litter was significantly greater than controls in the 500 mg/kg/day dose group, & mean absolute fetal head weight/litter for both sexes combined & for male fetuses was significantly reduced in the 250 & 500 mg/kg/day dose groups. No clearcut effects of treatment on mean absolute fetal heart weight/litter for males, females or for the sexes combined, relative fetal heart weight/litter for males or for the sexes combined, mean absolute female fetal head weight/litter or relative fetal head weight (males, females, or sexes combined)/litter were observed. In conclusion, in the teratology study, exposure of timed-pregnant CD rats to MO suspended in corn oil (0, 50, 100, 250, & 500 mg/kg/day) by gavage on gestational day 6-20, produced the following results: 1.A no effect level for maternal toxicity at 50 mg/kg/day, but significant maternal toxicity at 100, 250, & 500 mg/kg/day, with maternal mortality at both the 250 & 500 mg/kg/day dose levels. 2.A no effect level for embryo & fetal toxicity at 50 & 100 mg/kg/day, significant embryo toxicity at 500 mg/kg/day, & significant fetotoxicity at 250 & 500 mg/kg/day. 3.No clearcut teratogenic effect at any dose level, but a trend toward an incr in the incidence of malformations as a result of a marginal incr in the % malformed fetuses/litter, observed at the 250 & 500 mg/kg/day dose levels. In addition to the teratology study, a preliminary evaluation of perinatal survival & postnatal growth to postnatal day 22 of rat pups exposed in utero to alpha-methyldopa on gestational days 6-20 & fostered to untreated mothers was also conducted. For this preliminary perinatal & postnatal evaluation, alpha-methyldopa was administered in corn oil by gavage at doses of 0, 100, 250, 500 or 750 mg/kg/day to timed-mated females (6-7/group) on gestational days 6-20. During treatment, dams exposed to alpha-methyldopa exhibited observable signs of toxicity, predominantly at doses of 250 mg/kg/day & greater; no treatment-related deaths occurred. Exposure to alpha-methyldopa significantly reduced maternal body weight & absolute liver weight at doses of 250 mg/kg/day & above, & reduced maternal weight gain at doses of 500 mg/kg/day & above, but had no effect on relative maternal liver weight. Interestingly, alpha-methyldopa treatment significantly increased the length of the gestational period in the 500 & 750 mg/kg/day dose groups. On postnatal day 1, pups from vehicle or alpha-methyldopa-treated litters were examined for external malformations, weighed, sexed, & observed for clinical signs of toxicity & immediately reassigned by litter to untreated foster dams. Alpha-methyldopa had no significant effect on live litter size on /postnatal day/ 1, but by /postnatal day/ 4 perinatal survival exhibited a decreasing trend. In addition, when prenatal & perinatal mortality were considered together, the % cumulative mortality for both /postnatal day/ 1 & 4 exhibited an increasing trend. Alpha-methyldopa caused no evidence of malformation in /postnatal day/ 1 pups. However, avg pup body weight/litter exhibited a trend toward a decr on /postnatal day/ 1 that was evident but no longer significant after /postnatal day/ 4. Alpha-methyldopa treatment had no significant effect on absolute liver, brain or heart weight or on relative liver, brain, or heart weight of /postnatal day/ 22 pups. No overt differences in demeanor were observed in alpha-methyldopa-treated pups. /Alpha-Methyldopa/|Alpha-Methyldopa (MD) ... was evaluated for toxic & teratogenic effects in timed-pregnant CD-1 mice exposed to alpha-Methyldopa on gestational days (gd) 6-17 & sacrificed on gestational days 17. Prior to the initiation of the teratology study, a preliminary study was conducted in order to establish appropriate doses for use in the teratology study. Alpha-Methyldopa suspended in corn oil (0, 100, 250, 500, 750 mg/kg/day) was administered by gavage to timed-pregnant CD-1 mice on gestational days 6-17. Females were weighed & observed during daily treatment for clinical signs of toxicity. At sacrifice on gestational days 17, the gravid uterus of each dam was weighed. Following uterine dissection, the number & status of uterine implantation sites was recorded. ... A total of 21-25 dams (i.e., confirmed-pregnant females)/treatment group were evaluated in the study. During alpha-Methyldopa treatment, dams at all dose levels exhibited observable signs of clinical toxicity including rough coat, weight loss, lethargy, vaginal bleeding, & alopecia at various sites on the body. Maternal mortality was 0%, 0%, 0%, 4.3%, & 16% of confirmed-pregnant females in the vehicle through high dose groups. Alpha-Methyldopa at doses of 250 mg/kg/day or more caused significant depression of maternal body weight, weight gain, gravid uterine weight, & absolute maternal liver weight, with 100 mg/kg/day representing a no effect level for these parameters. Alpha-Methyldopa significantly increased embryotoxicity at doses of 500 mg/kg/day & above, as evidenced by a significant incr in the % resorptions/litter & other indices. Live litter size was significantly reduced at 750 mg/kg/day, & live fetal body weight was depressed in female fetuses at doses of 500 & 730 mg/kg/day Alpha-Methyldopa & in male fetuses at doses of 250 mg/kg/day alpha-Methyldopa & above. Alpha-Methyldopa significantly increased the % fetuses malformed/litter & the % female fetuses malformed/litter at both 500 & 750 mg/kg/day. The % male fetuses malformed/litter was not significantly affected by treatment. Alpha-Methyldopa caused a trend toward an incr in the incidence of skeletal malformations, but this effect was marginal & not dose-related. Alpha-Methyldopa had no effect on the incidence of external or visceral malformations. Relative fetal heart & whole head weight were not adversely affected by treatment. In conclusion, exposure of timed-pregnant CD-1 mice to alpha-methyldopa (0, 100, 250, 500, or 750 mg/kg/day) by gavage on gestational days 6-17, produced the following results: 1) Alpha-Methyldopa at the 100 mg/kg/day dose level caused mild clinical signs of maternal toxicity in a small number of animals but was a no effect level for other indices of maternal, embryo, & fetal toxicity. 2) At 250 mg/kg/day, alpha-methyldopa caused significant maternal toxicity, a noticeable but statistically insignificant incr in measures of embryotoxicity, & evidence of marginal fetotoxicity. 3) At 500 & 750 mg/kg/day, clear evidence of prenatal mortality & intrauterine growth retardation was observed in the presence of significant maternal toxicity &/or mortality. 4) MO caused a small but significant incr in the incidence of malformed fetuses/litter at both 500 & 750 mg/kg/day which appeared to primarily involve female fetuses. The % fetuses malformed & the number of litters with fetuses with skeletal malformations also exhibited a trend toward an incr. These effects were noted only in the presence of significant maternal, embryo, & fetal toxicity, & therefore may be secondary to generalized effects of alpha-methyldopa. 5) Evaluation of fetal whole head weight & heart weight indicated that whereas head weight was proportional to body weight for all dose groups, heart weight was not as affected by intrauterine growth retardation. In addition to the teratology study, a preliminary evaluation of perinatal survival & postnatal growth to postnatal day 21 of mouse pups exposed in utero to alpha-methyldopa on gestational days 6-17 & fostered to untreated mothers was also conducted. In this preliminary perinatal & postnatal evaluation, MD was administered in corn oil by gavage at doses of 0, 100, 250, 500, or 750 mg/kg/day to timed-mated females (6-7/group) on gestational days (gd) 6-17. During treatment, dams exposed to alpha-methyldopa exhibited observable signs of toxicity that consisted of weight loss & lethargy, primarily at doses of 250 mg/kg/day or greater; there were no treatment-related maternal deaths. Alpha-Methyldopa had no effect on maternal body weight but caused a trend toward a decr in maternal weight gain, with 100 mg/kg/day being a no effect level. Alpha-Methyldopa had no significant adverse effect on live litter size, survival & growth of live pups to /postnatal day/ 4, or pup survival & growth to /postnatal day/ 21. Evaluation of pup relative liver, heart, & brain weight on /postnatal day/ 21 indicated that liver & heart weight were unaffected, but suggested that in utero exposure to alpha-methyldopa at doses of 250 mg/kg/day & above may result, in the postnatal period, in depressed brain growth relative to body growth.

Patients with renal failure are more sensitive to the antihypertensive effect of methyldopa ...|In individuals who have sinoatrial node dysfunction, methyldopa may precipitate severe bradycardia and sinus arrest, including that which occurs with carotid sinus hypersensitivity.|... may cause asthma to pharmaceutical workers. /From table/

Low (less than 20%).

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.

For use in the treatment of hypertension.|FDA Label

Methyldopa (alpha-methyldopa or α-methyldopa) is a centrally active sympatholytic agent that has been used for more than 50 years for the treatment of hypertension. Methyldopa has been clearly linked to instances of acute and chronic liver injury that can be severe and even fatal.

Antihypertensive Agents

Adrenergic alpha-Agonists; Antihypertensive Agents; Sympatholytics|Methyldopa is indicated in the treatment of moderate to severe hypertension, including that complicated by renal disease. /Included in US product labeling/|Methyldopa is an effective antihypertensive agent when given in conjunction with a diuretic.|THE USUAL INITIAL DOSE OF METHYLDOPA IS 250 MG TWICE DAILY, AND THERE APPEARS TO BE LITTLE ADDNL EFFECT WITH DOSES OVER 2 G.|For more Therapeutic Uses (Complete) data for METHYLDOPA (6 total), please visit the HSDB record page.

Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction and is not recommended for use in patients with pheochromocytoma. Methyldopa is contraindicated in patients with active hepatic disease, such as acute hepatitis and active cirrhosis, and in patients in whom previous methyldopa therapy was associated with liver abnormalities or direct Coombs' positive hemolytic anemia. Methyldopa is contraindicated in patients receiving monoamine oxidase (MAO) inhibitors.|Patients who are receiving methyldopa and who undergo dialysis may occasionally become hypertensive after the dialysis, since the drug is dialyzable.|Positive direct antiglobulin (Coombs') test results have been reported in about 10-20% of patients receiving methyldopa, usually after 6-12 months of therapy. This phenomenon is dose related, with the lowest incidence in patients receiving 1 g or less of methyldopa daily. In most patients, a postive Coombs' test associated with mehtyldopa therapy is not clinically important. Reversal of the positive Coombs' test occurs within weeks to months after discontinuance of the drug and usually becomes negative within 6 months. Hemolytic anemia has only rarely occurred, although 2 deaths have been reported in patients with methyldopa-induced hemolytic anemia. If anemia or a positive Coombs' test occurs, appropriate laboratory studies should be performed to determine if hemolysis is present; if there is evidence of hemolytic anemia, the drug should be discontinued. Discontinuance of the drug alone or initiation of corticosteroid therapy has produced remission of methyldopa-induced hemolytic anemia.|Nasal congestion occurs commonly in patients receiving methyldopa. Decreased libido and impotence frequently occur in males during therapy with the drug.|For more Drug Warnings (Complete) data for METHYLDOPA (16 total), please visit the HSDB record page.

TOLERANCE SOMETIMES DEVELOPS IN UP TO THIRD OF INITIALLY RESPONSIVE PATIENTS.|DRUG RESISTANCE MAY DEVELOP WHEN METHYLDOPA IS USED ALONE BUT IS NOT USUALLY PROBLEM WHEN DIURETIC IS GIVEN CONCOMITANTLY.

Methyldopa is an aromatic-amino-acid decarboxylase inhibitor in animals and in man. Only methyldopa, the L-isomer of alpha-methyldopa, has the ability to inhibit dopa decarboxylase and to deplete animal tissues of norepinephrine. In man the antihypertensive activity appears to be due solely to the L-isomer. About twice the dose of the racemate (DL-alpha-methyldopa) is required for equal antihypertensive effect. Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Cardiac output usually is maintained without cardiac acceleration. In some patients the heart rate is slowed. Normal or elevated plasma renin activity may decrease in the course of methyldopa therapy. Methyldopa reduces both supine and standing blood pressure. Methyldopa usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.

Compounds that bind to and activate ADRENERGIC ALPHA-2 RECEPTORS. (See all compounds classified as Adrenergic alpha-2 Receptor Agonists.)|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. (See all compounds classified as Antihypertensive 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. (See all compounds classified as Sympatholytics.)

Absorption from the gastrointestinal tract is variable but averages approximately 50%.|Methyldopa is extensively metabolized. The known urinary metabolites are: α-methyldopa mono-O-sulfate; 3-0-methyl-α-methyldopa; 3,4-dihydroxyphenylacetone; α-methyldopamine; 3-0-methyl-α-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.|Renal cl=130 mL/min [healthy]|(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...|Methyldopa is partially absorbed from the GI tract. The degree of absorption varies among individuals and in the same patient from day to day, but generally about 50% of an oral dose is absorbed.

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.|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.

The plasma half-life of methyldopa is 105 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.

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.|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.

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. ACUTE/CHRONIC HAZARDS: When heated to decomposition this compound emits toxic fumes of nitrogen oxides. (NTP, 1992)

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. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

... AFTER DISCONTINUATION OF METHYLDOPA... HEMOLYTIC ANEMIA USUALLY RESOLVES WITHIN A MATTER OF WEEKS. SEVERE HEMOLYSIS MAY BE ATTENUATED BY TREATMENT WITH GLUCOCORTICOIDS.

...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.

Aldomet

100% AS AN ANTIHYPERTENSIVE AGENT (1976)

METHYLDOPA, USP (ALDOMET), IS AVAILABLE FOR ORAL ADMIN IN TABLETS CONTAINING 125, 250, OR 500 MG. MORE SOL PREPN, METHYLDOPATE HYDROCHLORIDE, USP (ALDOMET ESTER HYDROCHLORIDE), IS AVAILABLE IN 5-ML VIALS (50 MG/ML) FOR PARENTERAL USE.

L-Tyrosine, 3-hydroxy-.alpha.-methyl-: INACTIVE

METHYLDOPA WAS CHROMATOGRAPHED ON THIN-LAYER PLATES USING DIPHENYLAMINE AS A DETECTOR. SAMPLE WAS PLACED ON SILICA GEL 60F 254 THIN-LAYER PLATES & CHROMATOGRAPHED, IF POSSIBLE WITH AN ACIDIC MOBILE PHASE.|SPECTROPHOTOMETRIC METHOD FOR DETERMINATION OF METHYLDOPA IS DESCRIBED IN WHICH IT FORMS COLORED COMPLEX WITH CHLORANIL @ PH 9 WITH MAX ABSORPTION @ 358 NM.

A METHOD IS DESCRIBED USING REVERSE PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY & ELECTROCHEMICAL DETECTION FOR DETERMINATION OF MULTIPLE CATECHOLAMINES & THEIR CATECHOL METABOLITES IN PLASMA OR BRAIN TISSUE. ION-PAIRING CHROMATOGRAPHY WITH HNO3 OR TCA AS THE MOBILE PHASE PERMITTED SEPARATION & QUANTITATION OF ALPHA-METHYLDOPA.|A GAS CHROMATOGRAPHIC-MASS SPECTROMETRIC METHOD FOR DETERMINATION OF ALPHA-METHYLDOPA IN BLOOD & URINE INVOLVES STABLE ISOTOPE DILUTION USING ALPHA-TRIDEUTERIO-METHYLDOPA AS INTERNAL STD. REVERSE PHASE CHROMATOGRAPHY ON SMALL COLUMNS OF LIPIDEX 5000 IS USED TO REMOVE LIPIDS FROM PLASMA EXTRACTS & FOR PURIFICATION OF URINE SAMPLES PRIOR TO THEIR DERIVATIZATION.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Pharmaceuticals