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The following information was generated from the Hazardous Substances Data Bank (HSDB), a database of the National
Library of Medicine's TOXNET system (http://toxnet.nlm.nih.gov) on January 12, 2012. Query: Records containing the term 555 30 6 1 NAME: METHYLDOPA HSN: 218 RN: 555-30-6 HUMAN HEALTH EFFECTS: TOXICITY SUMMARY: 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.[International Programme on Chemical Safety; Poisons Information Monograph: Methyldopa (PIM 342) (1992) Available from, as of October 24, 2005: http://www.inchem.org/pages/pims.html] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS: ...ADVERSE REACTIONS INCL DRUG FEVER &, RARELY, GRANULOCYTOPENIA & THROMBOCYTOPENIA.[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 709] **PEER REVIEWED** SALT & WATER OFTEN ARE GRADUALLY RETAINED WITH PROLONGED USE OF METHYLDOPA ...[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 787] **PEER REVIEWED** ... METHYLDOPA PRODUCES SEDATION THAT IS LARGELY TRANSIENT.[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and
Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 787] **PEER REVIEWED** 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.[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 787] **PEER REVIEWED** AT LEAST 20% OF PATIENTS WHO RECEIVE METHYLDOPA FOR A YEAR DEVELOP A POSITIVE COOMBS' TEST (ANTIGLOBULIN TEST) THAT IS DUE TO AUTOANTIBODIES DIRECTED AGAINST THE RH LOCUS ON THE PATIENTS' ERYTHROCYTES. THE DEVELOPMENT OF A POSITIVE COOMBS' TEST PER SE, HOWEVER, IS NOT AN INDICATION TO STOP TREATMENT WITH METHYLDOPA; 1-5% OF THESE PATIENTS WILL DEVELOP A HEMOLYTIC ANEMIA WHICH REQUIRES PROMPT DISCONTINUATION OF THE DRUG. ... ADVERSE EFFECTS THAT ARE EVEN MORE RARE INCLUDE LEUKOPENIA, THROMBOCYTOPENIA, RED CELL APLASIA, LUPUS ERYTHEMATOSUS-LIKE SYNDROME, LICHENOID AND GRANULOCMATOUS SKIN ERUPTIONS, MYOCARDITIS, RETROPERITONEAL FIBROSIS, PANCREATITIS, DIARRHEA, AND MALABSORPTION.[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 788] **PEER REVIEWED** SIDE EFFECTS CONSEQUENT TO ITS BLOCKADE OF SYMPATHETIC NERVES INCL...NAUSEA, WEAKNESS & HEADACHE, BRADYCARDIA...DIARRHEA, & IMPOTENCE. OTHER SIDE EFFECTS INCL...DECR LIBIDO IN MALES, BREAST ENLARGEMENT, & PARESTHESIAS. ...IT MAY /RARELY/ CAUSE...PARKINSONISM, ARTHRALGIA, & MYALGIA. ...OCCASIONALLY JAUNDICE MAY OCCUR.[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 837] **PEER REVIEWED** ...CONTROLLED STUDY /WAS CONDUCTED/ IN WHICH 122 WOMEN WITH HYPERTENSION WERE TREATED WITH THIS DRUG. ONLY ONE /FETAL/ MALFORMATION OCCURRED (ABSENT KIDNEY WITH 2 UMBILICAL VESSELS). A BETTER PREGNANCY OUTCOME WAS ASSOCIATED WITH THE TREATMENT.[Shepard, T. H. Catalog of Teratogenic Agents. 3rd ed. Baltimore, MD.: Johns Hopkins University Press, 1980., p. 221] **PEER REVIEWED** A 68-YR OLD MAN UNDERGOING ANTIHYPERTENSIVE TREATMENT WITH METHYLDOPA DEVELOPED DIARRHEA & DIABETIC KETOACIDOSIS DURING HIS FIRST BRIEF TREATMENT; ABDOMINAL PAIN & DIABETIC KETOACIDOSIS DURING THE SECOND; & CHRONIC PANCREATITIS WITH EXOCRINE INSUFFICIENCY, ENDOCRINE INSUFFICIENCY & HEAVY CALCIFICATION OVER 30 MO. THERE HAD BEEN NO SUGGESTION OF PANCREATIC OR BILIARY TRACT DISEASE BEFORE HE RECEIVED METHYLDOPA, & BILIARY TRACT DISEASE WAS EXCLUDED BY SUBSEQUENT INVESTIGATIONS. METHYLDOPA-INDUCED PANCREATITIS HAS BEEN RECOGNIZED ONLY RECENTLY DESPITE WIDESPREAD USE OF THE DRUG.[RAMSAY LE ET AL; PRACTITIONER 226 (1368): 1166 (1982)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/7111151?dopt=Abstract" target=new>PubMed Abstract IN 2 PATIENTS WITH RETROPERITONEAL FIBROSIS COMPUTERIZED TOMOGRAPHY WAS USED FOR DIAGNOSIS AND/OR POSTOPERATIVE FOLLOW-UP. METHYLDOPA IS POSTULATED AS THE CAUSATIVE AGENT IN ONE CASE.[KRINSKY S ET AL; SOUTH MED J 76 (4): 517 (1983)] **PEER REVIEWED** <a
href="http://www.ncbi.nlm.nih.gov/pubmed/6836371?dopt=Abstract" target=new>PubMed Abstract IMMUNE HEMOLYTIC ANEMIA AND CHRONIC ACTIVE HEPATITIS DEVELOPED CONCURRENTLY IN 76-YR-OLD MAN AFTER PROLONGED THERAPY WITH METHYLDOPA. BOTH DISAPPEARED FOLLOWING CESSATION OF TREATMENT AND A SHORT COURSE OF A HIGH DOSE CORTICOSTEROID. INHIBITION OF T-SUPPRESSOR LYMPHOCYTE FUNCTION BY METHYLDOPA MAY BE INSTRUMENTAL IN THE EMERGENCE OF AUTOIMMUNE COMPLICATIONS FOLLOWING USAGE OF THE DRUG.[SHALEV O ET AL; ARCH INTERN MED 143 (3): 592 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6830396?dopt=Abstract" target=new>PubMed Abstract ... one-third of ... patients were found to have sexual disturbances after methyldopa treatment ranging from a decrease in libido, inability to maintain an erection, and difficulty in ejaculation.[Thomas, J.A., K.S. Korach, J.A. McLachlan. Endocrine Toxicology. New York, NY: Raven Press, Ltd., 1985., p. 310] **PEER REVIEWED** Fever occurs in 1-6% of patients taking methyldopa. /From table/[Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995., p. 6-9] **PEER REVIEWED** Methyldopa hepatitis occurs more commonly in patients > 35 yr and predominantly affects females. Acute hepatic injury has appeared within 4 wk of therapy in 50% of the patients reported and within 4-12 wk in 25$ of the cases. ... The fatality rate from acute hepatic injury is estimated to be 10%. /From table/[Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995., p. 26-10] **PEER REVIEWED** DRUG WARNINGS: 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.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1512] **PEER REVIEWED** Patients who are receiving methyldopa and who undergo dialysis may occasionally become hypertensive after the dialysis, since the drug is dialyzable.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1512] **PEER REVIEWED** 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.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1511] **PEER REVIEWED** Nasal congestion occurs commonly in patients receiving methyldopa. Decreased libido and impotence frequently occur in males during therapy with the drug.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1511] **PEER REVIEWED** Adverse GI effects including nausea, vomiting, diarrhea, dry mouth, distention, constipation, flatus, and sore or "black" tongue have been reported during methyldopa therapy. Pancreatitis has also occurred.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1511] **PEER REVIEWED** Although appropriate studies on the relationship of age to the effects of methyldopa have not been performed in the geriatric population, the elderly my be more sensitive to the hypotensive and sedative effects. In addition, elderly patients are more likely to have age-related renal function impairment, which may require lower doses in patients receiving methyldopa.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Orthostatic hypotension with attendant dizziness, lightheadedness, and symptoms of cerebrovascular insufficiency may occur during methyldopa therapy and is an indication for dosage reduction. Orthostatic hypotension may be less pronounced with methyldopa than with guanethidine or ganglionic blocking agents but may be more severe than with reserpine, clonidine, hydralazine, propranolol, or thiazides. Syncope in older patients may be related to an increased sensitivity to methyldopa and advanced arteriosclerotic vascular disease and may be avoided by using lower dosages.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1511] **PEER REVIEWED** The most common adverse effect of methyldopa is drowsiness which occurs within the first 48-72 hours of therapy and may disappear with continued administration of the drug. Sedation commonly recurs when dosage is increased. A persistent decrease in mental acuity, including impaired ability to concentrate, lapses of memory, and difficulty in performing simple calculations, may occur and usually necessitates withdrawal of the drug. Other adverse nervous system effects which occur early in therapy include vertigo, headache, asthenia, and weakness.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1511] **PEER REVIEWED** ITS ACTION IS ERRATIC & THIRD OF TREATED PT MAY NOT RESPOND TO THE DRUG. ... METHYLDOPA IS CONTRAINDICATED IN PRESENCE OF ACTIVE LIVER
DISEASE & IN PERSONS KNOWN TO BE SENSITIVE TO DRUG.[Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980., p. 786] **PEER REVIEWED** DISADVANTAGE OF METHYLDOPA IS WIDE RANGE OF EFFECTIVE DOSAGE (REQUIRING DOSE TITRATION) & HIGH COST.[American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977., p. 54] **PEER REVIEWED** METHYLDOPATE HYDROCHLORIDE IS USED ONLY RARELY TO TREAT HYPERTENSIVE CRISES BECAUSE OF ITS ERRATIC ONSET OF ACTION. IN ADDITION, THE SEDATIVE EFFECT MAY INTERFERE WITH EVALUATION OF MENTAL STATUS. /METHYLDOPATE HYDROCHLORIDE/[American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 4th ed. Chicago: American Medical Association, 1980., p. 570] **PEER REVIEWED** IN PRESENCE OF RENAL INSUFFICIENCY, DELAYED EXCRETION MAY RESULT IN DRUG ACCUMULATION. ... METHYLDOPA OCCASIONALLY PRODUCES SYMPTOMATIC ORTHOSTATIC HYPOTENSION, & PATIENT SHOULD BE INFORMED OF THIS POSSIBILITY. ... HEPATITIS IS USUALLY MILD & IS GENERALLY REVERSIBLE FOLLOWING DISCONTINUATION OF METHYLDOPA BUT, IN FEW INSTANCES, RE-EXPOSURE TO DRUG CAUSED FATAL HEPATIC NECROSIS.[American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 4th ed. Chicago: American Medical Association, 1980., p. 570] **PEER REVIEWED** METHYLDOPA & ITS METABOLITES...IN BLOOD & URINE CAN CAUSE FALSE-POSITIVE TESTS FOR PHEOCHROMOCYTOMA.[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 709] **PEER REVIEWED** PRELIMINARY RESULTS ARE PRESENTED THAT TREATMENT OF MOTHERS WITH METHYLDOPA DURING LATE PREGNANCY MAY SEVERELY INTERFERE WITH FETAL CEREBRAL MONOAMINE METABOLISM.[BODIS J ET AL; LANCET 2: 498 (1982)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6125663?dopt=Abstract" target=new>PubMed Abstract THE REPORTED INCIDENCES OF METHYLDOPA-INDUCED HEPATITIS AND HEMOLYTIC ANEMIA IS NOTABLY SMALL; HOWEVER, PRACTITIONERS SHOULD BE AWARE OF ITS ASSOCIATION WITH THESE DISORDERS.[BRELAND BD, HICKS GS JR; DRUG INTELL CLIN PHARM 16 (6): 489 (1982)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/7094845?dopt=Abstract" target=new>PubMed Abstract Maternal Medication usually Compatible with Breast-Feeding: Methyldopa: Reported Sign or Symptom in Infant or Effect on Lactation: None. /From Table 6/[Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 141 (1994)] **PEER REVIEWED** POPULATIONS AT SPECIAL RISK: Patients with renal failure are more sensitive to the antihypertensive effect of methyldopa ...[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 787] **PEER REVIEWED** In individuals who have sinoatrial node dysfunction, methyldopa may precipitate severe bradycardia and sinus arrest, including that which occurs with carotid sinus hypersensitivity.[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The
Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 787] **PEER REVIEWED** ... may cause asthma to pharmaceutical workers. /From table/[Rom, W.N. (ed.). Environmental and Occupational Medicine. 2nd ed. Boston, MA: Little, Brown and Company, 1992., p. 424] **PEER REVIEWED** EMERGENCY MEDICAL TREATMENT: EMERGENCY MEDICAL TREATMENT: EMT COPYRIGHT DISCLAIMER: Portions of the POISINDEX(R) and MEDITEXT(R) database have been provided here for general reference. THE COMPLETE POISINDEX(R) DATABASE OR MEDITEXT(R) DATABASE SHOULD BE CONSULTED FOR ASSISTANCE IN THE DIAGNOSIS OR TREATMENT OF SPECIFIC CASES. The use of the POISINDEX(R) and MEDITEXT(R) databases is at your sole risk. The POISINDEX(R) and MEDITEXT(R) databases are provided "AS IS" and "as available" for use, without warranties of any kind, either expressed or implied. Micromedex makes no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the POISINDEX(R) and MEDITEXT(R) databases. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Micromedex does not assume any responsibility or risk for your use of the POISINDEX(R) or MEDITEXT(R) databases. Copyright 1974-2011 Thomson MICROMEDEX. All Rights Reserved. Any duplication, replication, "downloading," sale, redistribution or other use for commercial purposes is a violation of Micromedex' rights and is strictly prohibited.<p>The following Overview, *** METHYLDOPA ***, is relevant for this HSDB record chemical. LIFE SUPPORT: o This overview assumes that basic life support measures have been instituted. CLINICAL EFFECTS: 0.2.1 SUMMARY OF EXPOSURE A) WITH POISONING/EXPOSURE 1) Acute overdosage of methyldopa may result in nausea, vomiting, diarrhea, bradycardia, hypothermia, dry mouth, hypotension, dizziness, weakness, lethargy, coma and bradycardia. 0.2.5 CARDIOVASCULAR A) WITH POISONING/EXPOSURE 1) Severe hypotension and bradycardia may be noted. 0.2.7 NEUROLOGIC A) WITH POISONING/EXPOSURE 1) CNS depression and coma may be noted. 0.2.20 REPRODUCTIVE A) Pregnancy Category C B) Methyldopa crosses the placenta and appears in breast milk in small amounts. LABORATORY: A) Plasma methyldopa levels are not clinically useful. B) No specific lab work (CBC, urinalysis, electrolytes) is needed unless otherwise indicated. TREATMENT OVERVIEW: 0.4.2 ORAL/PARENTERAL EXPOSURE A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
B) MONITOR VITAL SIGNS regularly, especially blood pressure. C) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response. D) ATROPINE: ADULT DOSE: BRADYCARDIA: 0.5 to 1 mg IV every 5 min. ASYSTOLE: 1 mg IV every 5 min. Maximum total dose 3 mg or 0.04 mg/kg. Minimum single dose 0.5 mg. PEDIATRIC DOSE: 0.02 mg/kg IV repeat every 5 min, minimum single dose 0.1 mg; maximum single dose child 0.5 mg, adolescent 1 mg; maximum total dose 1 mg child, 2 mg adolescent. E) HEMODIALYSIS or HEMOPERFUSION - Although there are no cases of use of these procedures in overdose, they may be of value following severe intoxication refractory to conventional therapy; however, good supportive care is generally all that is indicated. RANGE OF TOXICITY: A) Insufficient data in the literature exists to accurately assess the minimum toxic or lethal dose. B) An adult died following acute ingestion of 25 grams of methyldopa. C) Adults have developed coma, hypotension, bradycardia and hypothermia after ingestions ranging from 2.5 grams to 45 grams, with ultimate recovery. ANTIDOTE AND EMERGENCY TREATMENT: ... AFTER DISCONTINUATION OF METHYLDOPA... HEMOLYTIC ANEMIA USUALLY RESOLVES WITHIN A MATTER OF WEEKS. SEVERE HEMOLYSIS MAY BE ATTENUATED BY TREATMENT WITH GLUCOCORTICOIDS.[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 788] **PEER REVIEWED** ANIMAL TOXICITY STUDIES: TOXICITY SUMMARY: 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.[International Programme on Chemical Safety; Poisons Information Monograph: Methyldopa (PIM 342) (1992) Available from, as of October 24, 2005: http://www.inchem.org/pages/pims.html] **PEER REVIEWED** NON-HUMAN TOXICITY EXCERPTS: METHYLDOPA...PRODUCES SEDATION IN LAB ANIMALS...& HAS BEEN SHOWN TO HAVE NUMBER OF OTHER CNS EFFECTS.[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 708] **PEER REVIEWED** ERECTILE IMPOTENCE IS A COMMONLY REPORTED UNDESIRED SIDE EFFECT IN PT TREATED FOR HYPERTENSION WITH ALPHA-METHYLDOPA. HOWEVER, THE MECHANISM OF THAT DYSFUNCTION HAS NOT BEEN DETERMINED. IN 12 DAYS OF DAILY IP INJECTIONS, 300 MG/KG, OF ALPHA-METHYLDOPA ON ADULT MALE, LONG EVANS RATS AND THEIR AGE-MATCHED SALINE CONTROLS EFFECT OF THE DRUG UPON COPULATION, PENILE REFLEXES AND TISSUE CATECHOLAMINES WAS MEASURED. SIGNIFICANT DIFFERENCES BETWEEN CONTROL AND EXPERIMENTAL ANIMALS IN ALL PARAMETERS STUDIED.[MELMAN A ET AL; THE EFFECT OF CHRONIC ALPHA-METHYLDOPA UPON SEXUAL FUNCTION IN THE ADULT MALE RAT; J UROL 129(3) 643 (1983)] **PEER REVIEWED** IN ANESTHETIZED DOGS, ALPHA-METHYLDOPA DECR PLASMA VASOPRESSIN CONCN FROM A CONTROL VALUE OF 17 TO 7.4 PG/ML @ 120 MIN POSTINFUSION. PLASMA RENIN ACTIVITY DECR FROM 13.3-7 NG/ML/3 HR @ 120 MIN POSTINFUSION. BLOOD PRESSURE AND HEART RATE WERE NOT AFFECTED BY THE INFUSION. THE POSSIBILITY THAT VASOPRESSIN INHIBITION IS MEDIATED BY CENTRAL ALPHA-ADRENERGIC ACTIVATION BY ALPHA-METHYLNOREPINEPHRENE, A METABOLITE OF METHYLDOPA.[BARBIERI C ET AL; EFFECT OF ALPHA-METHYLDOPA ADMINISTRATION ON VASOPRESSIN SECRETION IN DOGS; PROC SERONO SYMP 50(ENDOCRINOL HYPERTENS) 423 (1982)] **PEER REVIEWED** Pregnant CD rats were administered methyldopa (MD) suspended in corn oil by gavage at doses of 0, 50, 100, 250, or 500 mg/kg/day on gestation day 6 through 20. Clinical signs of toxicity (lethargy, rough coat, vaginal bleeding) were observed in the dams during treatment at 100, 250 and 500 mg/kg/day, with increased maternal mortality at both the 250 and 500 mg/kg/day levels. At gestational day 20, the dams were sacrificed and their fetuses were examined. MD significantly increased embryotoxicity at 500 mg/kg/day, as evidenced by an increase in the percentage of resorptions per litter. Average fetal body weight per litter decreased significantly as the dose of MD increased, in the 100, 250, and 500 mg/kg/day groups compared with controls. MD was not associated with any specific malformation or group of malformations at any of the dose levels in this study.[George JD et al; Report (NTP 86-128):128 PP (1986)] **QC REVIEWED** Alpha-methyldopa (MD) suspended in corn oil at 0, 100, 250, 500, or 750 mg/kg/day dose levels was administered by gavage to pregnant CD-1 mice (21-25 animals per dose group) on gestational days 6-17. MD caused maternal toxicity and embryolethality at 250 mg/kg/day. A significant increase in the number of resorptions was observed at the 500 and 750 mg/kg/day dose levels. At 500 and 750 mg/kg/day, clear evidence of prenatal mortality and intrauterine growth retardation as well as an incidence of malformed fetuses was observed.[George JD et al; Report (NTP 87-035):373 PP (1986)] **QC REVIEWED**
... 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 sesquihydrate/[Toxicology & Carcinogenesis Studies of alpha-Methyldopa Sesquihydrate in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 348 (1989) NIH Publication No. 89-2803 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709] **QC REVIEWED** NATIONAL TOXICOLOGY PROGRAM STUDIES: 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. ...[Toxicology & Carcinogenesis Studies of alpha-Methyldopa Sesquihydrate in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 348 (1989) NIH Publication No. 89-2803 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709] **QC REVIEWED** 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/[Department of Health & Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Teratologic Evaluation of Alpha-Methyldopa (CAS No. 555-30-6) Administered to CD Rats on Gestational Days 6 through 20, NTP Study No. TER85090 (April 1, 1986) Available from, as of August 16, 2002: http://ntp.niehs.nih.gov/index.cfm?objectid=0847FF31-90CC-C685-88B4D7EAC97 5BD44] **QC REVIEWED** 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.[Department of Health & Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Teratologic Evaluation of Alpha-Methyldopa (CAS No. 555-30-6) Administered to CD-1 Mice on Gestational Days 6 through 17, NTP Study No. TER86091 (January 9, 1987) Available from, as of August 16, 2002: http://ntp.niehs.nih.gov/index.cfm?objectid=0847FF31-90CC-C685-88B4D7EAC97
5BD44] **QC REVIEWED** NON-HUMAN TOXICITY VALUES: LD50 Rat oral 5000 mg/kg[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1244] **PEER REVIEWED** LD50 Rat ip 300 mg/kg[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1244] **PEER REVIEWED** LD50 Mouse ip 150 mg/kg[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1244] **PEER REVIEWED** LD50 Mouse iv 1700 mg/kg[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1244] **PEER REVIEWED** LD50 Rabbit oral 713 mg/kg[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1244] **PEER REVIEWED** LD50 Rabbit iv 713 mg/kg[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1244] **PEER REVIEWED** 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.sear chresults&searchterm=41372-08-1][Available from: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searc hresults&searchterm=41372-08-1] **QC REVIEWED** METABOLISM/PHARMACOKINETICS: METABOLISM/METABOLITES: 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/[Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. D-55] **PEER REVIEWED** METHYLDOPA...UNDERGOES DECARBOXYLATION & BETA-HYDROXYLATION IN MOUSE & RABBIT BRAIN TO YIELD ALPHA-METHYLNORADRENALINE.[Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968., p. 180] **PEER REVIEWED**
...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%).[Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968., p. 180] **PEER REVIEWED** A REVIEW ON THE METAB OF ALPHA-METHYLDOPA.[MUSCHOLL E; ALPHA METHYLDOPA INT SYMP 20 (1981)] **PEER REVIEWED** ABSORPTION, DISTRIBUTION & EXCRETION: (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.[Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968., p. 180] **PEER REVIEWED** METHYLDOPA CROSSES THE PLACENTA...[American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 4th ed. Chicago: American Medical Association, 1980., p. 571] **PEER REVIEWED** 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.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1510] **PEER REVIEWED** BIOLOGICAL HALF-LIFE: 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.[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 787] **PEER REVIEWED** 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.[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980., p. 795] **PEER REVIEWED** 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.[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 709] **PEER REVIEWED** MECHANISM OF ACTION: METHYLDOPA...HAS HYPOTENSIVE ACTION INDEPENDENT OF ITS ANTIADRENERGIC ACTIONS; THIS IS PROBABLY PARTLY CENTRAL DEPRESSANT ACTION @ VASOMOTOR CENTER & PARTLY PERIPHERAL ACTION OF UNKNOWN MECHANISM.[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 836] **PEER REVIEWED**
... 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.[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 786] **PEER REVIEWED** 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.[PETTY MA, DE JONG W; CLIN SCI SUPPL 63 (8): 293 (1982)] **PEER REVIEWED** A REVIEW ON THE MECHANISM OF ACTION.[KRONEBERG G; ALPHA-METHYLDOPA INT SYMP 6 (1981)] **PEER REVIEWED** INTERACTIONS: LEVODOPA...REPORTED TO AUGMENT ANTIHYPERTENSIVE EFFECT OF METHYLDOPA IN MAN.[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 708] **PEER REVIEWED** 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...[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 707] **PEER REVIEWED** METHYLDOPA...REPORTED TO AUGMENT AMPHETAMINE-INDUCED HYPERACTIVITY IN MICE...[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 708] **PEER REVIEWED** 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.[Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978., p. 557] **PEER REVIEWED** Increases mean tolbutamide half-life by 24% in 1 study. /From table/[Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995., p. 48-39] **PEER REVIEWED** Concurrent use /with alcohol or central nervous system depression-producing medications/ may enhance the CNS depressant effects of either these medications or methyldopa.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Concurrent use /of coumarin- or indandione-derivative anticoagulants/ with methyldopa may increase the anticoagulant effect of these medications; adjustment of anticoagulant dosage based on prothrombin-time
determinations is recommended.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** /Concurrent use with tricyclic antidepressants/ may reduce antihypertensive effects of methyldopa; the patient should be carefully monitored to confirm that the desired effect is being obtained.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Antihypertensive effects of methyldopa may be reduced when it is used concurrently with these medications; indomethacin, and possibly other nonsteroidal anti-inflammatory drugs (NSAIDs), may antagonize the antihypertensive effect by inhibiting renal prostaglandin synthesis and/or by causing sodium and fluid retention; the patient should be carefully monitored to confirm that the desired effect is being obtained.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Concurrent use /with appetite suppressants, with the exception of fenfluramine/ may decrease the hypotensive effects of methyldopa.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** /When taken concurrently with estrogens/ estrogen-induced fluid retention tends to increase blood pressure.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Concurrent use /with fenfluramine/ may increase the hypotensive effects of methyldopa.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Concurrent use of haloperidol with methyldopa may cause unwanted mental effects such as disorientation and slowed or difficult thought process.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Hypotensive effects may be potentiated when these medications /other hypotension-producing medications/ are used concurrently with methyldopa; although some antihypertensive and/or diuretic combinations are frequently used for therapeutic advantage, dosage adjustments may be necessary during concurrent use.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Concurrent use /of levodopa/ with methyldopa may alter the antiparkinsonian effects of levodopa and may also produce additive toxic CNS effects such as psychosis.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Concurrent use /of lithium/ with methyldopa may increase the risk of lithium toxicity, even though serum lithium concentrations remain within the recommended therapeutic range.[USP Convention. USPDI - Drug
Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Methyldopa may cause hyperexcitability in patients receiving monoamine oxidase (MAO) inhibitors /including furazolidone, procarbazine, and selegiline/; headache, severe hypertension, and hallucinations have been reported.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Concurrent use with sympathomimetic pressor amines may decrease the hypotensive effect of methyldopa and potentiate the pressor effect of these medications; if concurrent use of cocaine, norepinephrine, or phenylephrine is indicated, caution is required, and only very small initial doses should be administered.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** PHARMACOLOGY: THERAPEUTIC USES: Adrenergic alpha-Agonists; Antihypertensive Agents; Sympatholytics[National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)] **PEER REVIEWED** Methyldopa is indicated in the treatment of moderate to severe hypertension, including that complicated by renal disease. /Included in US product labeling/[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2000] **PEER REVIEWED** Methyldopa is an effective antihypertensive agent when given in conjunction with a diuretic.[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 788] **PEER REVIEWED** THE USUAL INITIAL DOSE OF METHYLDOPA IS 250 MG TWICE DAILY, AND THERE APPEARS TO BE LITTLE ADDNL EFFECT WITH DOSES OVER 2 G.[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 788] **PEER REVIEWED** MECHANISM & ACTIONS OF ALPHA METHYLDOPA & ANTIHYPERTENSIVE TREATMENT ARE DISCUSSED.[ZANCHETTI A (ED); IN: CLIN EXP PHARMACOL PHYSIOL, SUPPL (4) (1978)] **QC REVIEWED** IN THE TREATMENT OF CARCINOID TUMOR /PRC: FORMER USE/[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 837] **QC REVIEWED** DRUG WARNINGS: 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.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1512] **PEER REVIEWED** Patients who are receiving methyldopa and who undergo dialysis may occasionally become hypertensive after the dialysis, since the drug is dialyzable.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1512] **PEER REVIEWED** 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.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1511] **PEER REVIEWED** Nasal congestion occurs commonly in patients receiving methyldopa. Decreased libido and impotence frequently occur in males during therapy with the drug.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1511] **PEER REVIEWED** Adverse GI effects including nausea, vomiting, diarrhea, dry mouth, distention, constipation, flatus, and sore or "black" tongue have been reported during methyldopa therapy. Pancreatitis has also occurred.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1511] **PEER REVIEWED** Although appropriate studies on the relationship of age to the effects of methyldopa have not been performed in the geriatric population, the elderly my be more sensitive to the hypotensive and sedative effects. In addition, elderly patients are more likely to have age-related renal function impairment, which may require lower doses in patients receiving methyldopa.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Orthostatic symptoms of therapy and may be less hypotension with attendant dizziness, lightheadedness, and cerebrovascular insufficiency may occur during methyldopa is an indication for dosage reduction. Orthostatic hypotension pronounced with methyldopa than with guanethidine or
ganglionic blocking agents but may be more severe than with reserpine, clonidine, hydralazine, propranolol, or thiazides. Syncope in older patients may be related to an increased sensitivity to methyldopa and advanced arteriosclerotic vascular disease and may be avoided by using lower dosages.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1511] **PEER REVIEWED** The most common adverse effect of methyldopa is drowsiness which occurs within the first 48-72 hours of therapy and may disappear with continued administration of the drug. Sedation commonly recurs when dosage is increased. A persistent decrease in mental acuity, including impaired ability to concentrate, lapses of memory, and difficulty in performing simple calculations, may occur and usually necessitates withdrawal of the drug. Other adverse nervous system effects which occur early in therapy include vertigo, headache, asthenia, and weakness.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1511] **PEER REVIEWED** ITS ACTION IS ERRATIC & THIRD OF TREATED PT MAY NOT RESPOND TO THE DRUG. ... METHYLDOPA IS CONTRAINDICATED IN PRESENCE OF ACTIVE LIVER DISEASE & IN PERSONS KNOWN TO BE SENSITIVE TO DRUG.[Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980., p. 786] **PEER REVIEWED** DISADVANTAGE OF METHYLDOPA IS WIDE RANGE OF EFFECTIVE DOSAGE (REQUIRING DOSE TITRATION) & HIGH COST.[American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977., p. 54] **PEER REVIEWED** METHYLDOPATE HYDROCHLORIDE IS USED ONLY RARELY TO TREAT HYPERTENSIVE CRISES BECAUSE OF ITS ERRATIC ONSET OF ACTION. IN ADDITION, THE SEDATIVE EFFECT MAY INTERFERE WITH EVALUATION OF MENTAL STATUS. /METHYLDOPATE HYDROCHLORIDE/[American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 4th ed. Chicago: American Medical Association, 1980., p. 570] **PEER REVIEWED** IN PRESENCE OF RENAL INSUFFICIENCY, DELAYED EXCRETION MAY RESULT IN DRUG ACCUMULATION. ... METHYLDOPA OCCASIONALLY PRODUCES SYMPTOMATIC ORTHOSTATIC HYPOTENSION, & PATIENT SHOULD BE INFORMED OF THIS POSSIBILITY. ... HEPATITIS IS USUALLY MILD & IS GENERALLY REVERSIBLE FOLLOWING DISCONTINUATION OF METHYLDOPA BUT, IN FEW INSTANCES, RE-EXPOSURE TO DRUG CAUSED FATAL HEPATIC NECROSIS.[American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 4th ed. Chicago: American Medical Association, 1980., p. 570] **PEER REVIEWED** METHYLDOPA & ITS METABOLITES...IN BLOOD & URINE CAN CAUSE FALSE-POSITIVE TESTS FOR PHEOCHROMOCYTOMA.[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 709] **PEER REVIEWED** PRELIMINARY RESULTS ARE PRESENTED THAT TREATMENT OF MOTHERS WITH METHYLDOPA DURING LATE PREGNANCY MAY SEVERELY INTERFERE WITH FETAL CEREBRAL MONOAMINE METABOLISM.[BODIS J ET AL; LANCET 2: 498 (1982)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6125663?dopt=Abstract" target=new>PubMed Abstract
THE REPORTED INCIDENCES OF METHYLDOPA-INDUCED HEPATITIS AND HEMOLYTIC ANEMIA IS NOTABLY SMALL; HOWEVER, PRACTITIONERS SHOULD BE AWARE OF ITS ASSOCIATION WITH THESE DISORDERS.[BRELAND BD, HICKS GS JR; DRUG INTELL CLIN PHARM 16 (6): 489 (1982)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/7094845?dopt=Abstract" target=new>PubMed Abstract Maternal Medication usually Compatible with Breast-Feeding: Methyldopa: Reported Sign or Symptom in Infant or Effect on Lactation: None. /From Table 6/[Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 141 (1994)] **PEER REVIEWED** INTERACTIONS: LEVODOPA...REPORTED TO AUGMENT ANTIHYPERTENSIVE EFFECT OF METHYLDOPA IN MAN.[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 708] **PEER REVIEWED** 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...[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 707] **PEER REVIEWED** METHYLDOPA...REPORTED TO AUGMENT AMPHETAMINE-INDUCED HYPERACTIVITY IN MICE...[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 708] **PEER REVIEWED** 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.[Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978., p. 557] **PEER REVIEWED** Increases mean tolbutamide half-life by 24% in 1 study. /From table/[Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995., p. 48-39] **PEER REVIEWED** Concurrent use /with alcohol or central nervous system depression-producing medications/ may enhance the CNS depressant effects of either these medications or methyldopa.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Concurrent use /of coumarin- or indandione-derivative anticoagulants/ with methyldopa may increase the anticoagulant effect of these medications; adjustment of anticoagulant dosage based on prothrombin-time determinations is recommended.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** /Concurrent use with tricyclic antidepressants/ may reduce antihypertensive effects of methyldopa; the patient should be carefully monitored to confirm that the desired effect is being obtained.[USP Convention. USPDI - Drug Information for the Health Care Professional.
17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Antihypertensive effects of methyldopa may be reduced when it is used concurrently with these medications; indomethacin, and possibly other nonsteroidal anti-inflammatory drugs (NSAIDs), may antagonize the antihypertensive effect by inhibiting renal prostaglandin synthesis and/or by causing sodium and fluid retention; the patient should be carefully monitored to confirm that the desired effect is being obtained.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Concurrent use /with appetite suppressants, with the exception of fenfluramine/ may decrease the hypotensive effects of methyldopa.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** /When taken concurrently with estrogens/ estrogen-induced fluid retention tends to increase blood pressure.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Concurrent use /with fenfluramine/ may increase the hypotensive effects of methyldopa.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Concurrent use of haloperidol with methyldopa may cause unwanted mental effects such as disorientation and slowed or difficult thought process.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Hypotensive effects may be potentiated when these medications /other hypotension-producing medications/ are used concurrently with methyldopa; although some antihypertensive and/or diuretic combinations are frequently used for therapeutic advantage, dosage adjustments may be necessary during concurrent use.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Concurrent use /of levodopa/ with methyldopa may alter the antiparkinsonian effects of levodopa and may also produce additive toxic CNS effects such as psychosis.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Concurrent use /of lithium/ with methyldopa may increase the risk of lithium toxicity, even though serum lithium concentrations remain within the recommended therapeutic range.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Methyldopa may cause hyperexcitability in patients receiving monoamine oxidase (MAO) inhibitors /including furazolidone, procarbazine, and selegiline/; headache, severe hypertension, and hallucinations have been reported.[USP Convention. USPDI - Drug Information for the Health Care
Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** Concurrent use with sympathomimetic pressor amines may decrease the hypotensive effect of methyldopa and potentiate the pressor effect of these medications; if concurrent use of cocaine, norepinephrine, or phenylephrine is indicated, caution is required, and only very small initial doses should be administered.[USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 2001] **PEER REVIEWED** DRUG TOLERANCE: TOLERANCE SOMETIMES DEVELOPS IN UP TO THIRD OF INITIALLY RESPONSIVE PATIENTS.[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 836] **PEER REVIEWED** DRUG RESISTANCE MAY DEVELOP WHEN METHYLDOPA IS USED ALONE BUT IS NOT USUALLY PROBLEM WHEN DIURETIC IS GIVEN CONCOMITANTLY.[American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977., p. 54] **PEER REVIEWED** ENVIRONMENTAL FATE & EXPOSURE: MILK CONCENTRATIONS: 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.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1510] **PEER REVIEWED** ENVIRONMENTAL STANDARDS & REGULATIONS: FDA REQUIREMENTS: 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).[21 CFR 200-299, 300-499, 820, and 860 (4/1/97)] **PEER REVIEWED** CHEMICAL/PHYSICAL PROPERTIES: MOLECULAR FORMULA: C10-H13-N-O4 **PEER REVIEWED** MOLECULAR WEIGHT:
211.22[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 1034] **PEER REVIEWED** COLOR/FORM: Minute, anhyd crystals from methanol[Budavari, S. (ed.). The Merck Index An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 1034] **PEER REVIEWED** WHITE TO YELLOWISH WHITE, FINE POWDER, WHICH MAY CONTAIN FRIABLE LUMPS[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 836] **PEER REVIEWED** ODOR: ODORLESS[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 836] **PEER REVIEWED** TASTE: ALMOST TASTELESS[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 836] **PEER REVIEWED** PH: pH of saturated aq soln about 5.0[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 1034] **PEER REVIEWED** SOLUBILITIES: In water @ 25 deg C: about 10 mg/ml; practically insol in common org solvents; sol in dil mineral acids[Budavari, S. (ed.). The Merck Index An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 1034] **PEER REVIEWED** Soluble in isopropanol, ethanol, and water.[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1244] **PEER REVIEWED** SPECTRAL PROPERTIES: Max absorption: 281 nm (e= 2780); Specific optical rotation (1 in 0.1 N HCl): -4.0 +/- 0.5 deg @ 23 deg C/D[Budavari, S. (ed.). The Merck Index An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 1034] **PEER REVIEWED** OTHER CHEMICAL/PHYSICAL PROPERTIES: Considerably hygroscopic; decomp @ approx 300 deg C; exists as sesquihydrate[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 1034] **PEER REVIEWED** Crystals from water /sesquihydrate/[Budavari, S. (ed.). The Merck Index An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 1034] **PEER REVIEWED** Sol in water @ 25 deg C: approx 10 mg/ml /D-form/[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 1034] **PEER REVIEWED**
Sol in water @ 25 deg C: approx 18 mg/ml /DL-form/[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 1034] **PEER REVIEWED** CHEMICAL SAFETY & HANDLING: HAZARDOUS DECOMPOSITION: When heated to decomposition it emits toxic fumes of nitroxides.[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1245] **PEER REVIEWED** STABILITY/SHELF LIFE: RELATIVELY STABLE IN BOTH LIGHT & AIR[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 836] **PEER REVIEWED** Methyldopa is decomposed by oxidizing agents.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1510] **PEER REVIEWED** STORAGE CONDITIONS: Methyldopa oral suspension should be stored in tight, light-resistant containers at a temperature less than 26 deg C and protected from freezing. Methyldopa tablets should be stored in well-closed containers at a temperature less than 40 deg C, preferably at 15-30 deg C.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1510] **PEER REVIEWED** DISPOSAL METHODS: 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. **PEER REVIEWED** OCCUPATIONAL EXPOSURE STANDARDS:
MANUFACTURING/USE INFORMATION: MAJOR USES: MEDICATION **QC REVIEWED** ANTIHYPERTENSIVE AGENT[SRI] **PEER REVIEWED** MANUFACTURERS: MSD Quimica de Puerto Rico, Inc., P.O. Box 601, Barceloneta, PR 00617, 1(787)846-4100. Production site: Barceloneta, PR 00617[SRI. 1998 Directory of Chemical Producers -United States of America. SRI International, Menlo Park, CA. 1998., p. 729] **PEER REVIEWED**
METHODS OF MANUFACTURING: 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).[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 1034] **PEER REVIEWED** 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[GENNARO. REMINGTON'S PHARM SCI 17TH ED 1985 p.846] **PEER REVIEWED** FORMULATIONS/PREPARATIONS: 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.[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980., p. 796] **PEER REVIEWED** CONSUMPTION PATTERNS: 100% AS AN ANTIHYPERTENSIVE AGENT (1976)[SRI] **PEER REVIEWED** U. S. PRODUCTION: (1972) PROBABLY GREATER THAN 4.54X10+5 GRAMS[SRI] **PEER REVIEWED** (1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS[SRI] **PEER REVIEWED** U. S. IMPORTS: (1975) 6.8X10+3 GRAMS (PRINCPL CUSTMS DISTS)[SRI] **PEER REVIEWED** (1983) 3.15X10+5 g[USITC. IMPORTS OF BENZENOID CHEM & PROD 1983 p.85] **QC REVIEWED** LABORATORY METHODS: CLINICAL LABORATORY METHODS: 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.[FREED CR, ASMUS PA; BRAIN TISSUE AND PLASMA ASSAY OF L-DOPA AND ALPHA-METHYLDOPA METABOLITES BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY WITH ELECTROCHEMICAL DETECTION; J NEUROCHEM 32(1) 163 (1979)] **PEER REVIEWED** 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.[SETCHELL KE ET AL; THE MEASUREMENT OF ALPHA-METHYLDOPA IN URINE AND PLASMA AS ITS N-BUTYL ESTER-PENTAFLUOROPROPIONATE DERIVATIVE USING STABLE ISOTOPE DILUTION GAS CHROMATOGRAPHY-MASS SPECTROMETRY; QUANT MASS SPECTROM LIFE SCI 2: 263 (1978)] **PEER REVIEWED** ANALYTIC LABORATORY METHODS: 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.[EGLI R, TANNER S; DIPHENYLAMINE IN THE MOBILE PHASE AS A UNIVERSAL DETECTION REAGENT IN THIN-LAYER CHROMATOGRAPHY; FRESENIUS Z ANAL CHEM 296(1) 45 (1979)] **PEER REVIEWED** SPECTROPHOTOMETRIC METHOD FOR DETERMINATION OF METHYLDOPA IS DESCRIBED IN WHICH IT FORMS COLORED COMPLEX WITH CHLORANIL @ PH 9 WITH MAX ABSORPTION @ 358 NM.[KORANY MA, WAHBI AA M; SPECTROPHOTOMETRIC DETERMINATION OF ISOPRENALINE SULFATE AND METHYLDOPA USING CHLORANIL; ANALYST (LONDON) 104(1235) 146 (1979)] **PEER REVIEWED** SPECIAL REFERENCES: SPECIAL REPORTS: 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)] SYNONYMS AND IDENTIFIERS: SYNONYMS: ALANINE, 3-(3,4-DIHYDROXYPHENYL)-2-METHYL-, L-(-)- **PEER REVIEWED** ALDOMET **PEER REVIEWED** ALDOMETIL **PEER REVIEWED** ALDOMIN **PEER REVIEWED** AMD **PEER REVIEWED** L-2-AMINO-2-METHYL-3-(3,4-DIHYDROXYPHENYL)PROPIONIC ACID[The Merck Index.
9th ed. Rahway, New Jersey: Merck & Co., Inc., 1976., p. 790] **PEER REVIEWED** BAYER 1440 L **PEER REVIEWED** BAYPRESOL **PEER REVIEWED** L(-)-BETA-(3,4-DIHYDROXYPHENYL)-ALPHA-METHYLALANINE[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED** L-3-(3,4-DIHYDROXYPHENYL)-2-METHYLALANINE[The Merck Index. 9th ed. Rahway, New Jersey: Merck & Co., Inc., 1976., p. 790] **PEER REVIEWED** DOPAMET **PEER REVIEWED** DOPATEC **PEER REVIEWED** DOPEGYT[The Merck Index. 9th ed. Rahway, New Jersey: Merck & Co., Inc., 1976., p. 790] **PEER REVIEWED** 3-HYDROXY-ALPHA-METHYL-L-TYROSINE[The Merck Index. 9th ed. Rahway, New Jersey: Merck & Co., Inc., 1976., p. 790] **PEER REVIEWED** HYPERPAX[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED** L-(ALPHA-MD)[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED** MEDOMET **PEER REVIEWED** ALPHA MEDOPA **PEER REVIEWED** MEDOPREN **PEER REVIEWED** METHOPLAIN **PEER REVIEWED** ALPHA-METHYL-BETA-(3,4-DIHYDROXYPHENYL)-L-ALANINE[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED** ALPHA-METHYL-L-3,4-DIHYDROXYPHENYLALANINE **PEER REVIEWED** L-(-)-ALPHA-METHYL-BETA-(3,4-DIHYDROXYPHENYL)ALANINE[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED**
L-ALPHA-METHYL-3,4-DIHYDROXYPHENYLALANINE[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED** (-)-METHYLDOPA[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED** ALPHA-METHYL DOPA[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED** ALPHA-METHYLDOPA, L-[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED** L-METHYLDOPA[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED** L-ALPHA-METHYLDOPA[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED** MK 351 **PEER REVIEWED** MK B51[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED** NCI-C55721[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED** NRC 2294[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED** PRESINOL[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER
REVIEWED** PRESOLISIN **PEER REVIEWED** SEDOMETIL[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED** SEMBRINA **PEER REVIEWED** L-TYROSINE, 3-HYDROXY-ALPHA-METHYL-[U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212] **PEER REVIEWED** ASSOCIATED CHEMICALS: Methyldopa sesquihydrate;41372-08-1 FORMULATIONS/PREPARATIONS: 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.[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980., p. 796] **PEER REVIEWED** ADMINISTRATIVE INFORMATION: HAZARDOUS SUBSTANCES DATABANK NUMBER: 218 LAST REVISION DATE: 20030305 LAST REVIEW DATE: Reviewed by SRP on 5/20/1999 UPDATE HISTORY: Complete Update on 03/05/2003, 1 field added/edited/deleted. Complete Update on 02/13/2002, 1 field added/edited/deleted. Complete Update on 01/14/2002, 1 field added/edited/deleted. Complete Update on 08/09/2001, 1 field added/edited/deleted. Complete Update on 10/19/2000, 2 fields added/edited/deleted. Complete Update on 03/28/2000, 1 field added/edited/deleted. Complete Update on 02/08/2000, 1 field added/edited/deleted. Complete Update on 02/02/2000, 1 field added/edited/deleted. Complete Update on 11/18/1999, 1 field added/edited/deleted. Complete Update on 09/21/1999, 1 field added/edited/deleted.
Complete Update on 08/26/1999, 1 field added/edited/deleted. Complete Update on 08/16/1999, 31 fields added/edited/deleted. Complete Update on 06/02/1998, 1 field added/edited/deleted. Complete Update on 12/18/1997, 3 fields added/edited/deleted. Complete Update on 03/11/1997, 3 fields added/edited/deleted. Complete Update on 05/10/1996, 1 field added/edited/deleted. Complete Update on 01/18/1996, 1 field added/edited/deleted. Complete Update on 12/19/1994, 1 field added/edited/deleted. Complete Update on 08/19/1994, 1 field added/edited/deleted. Complete Update on 11/01/1993, 1 field added/edited/deleted. Complete Update on 09/14/1993, 1 field added/edited/deleted. Field update on 12/11/1992, 1 field added/edited/deleted. Complete Update on 09/03/1992, 1 field added/edited/deleted. Complete Update on 09/26/1991, 2 fields added/edited/deleted. Complete Update on 10/22/1990, 4 fields added/edited/deleted. Complete Update on 09/08/1987, 36 fields added/edited/deleted.

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The following information was generated from the Hazardous Substances Data Bank (HSDB), a database of the National

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