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Identification
NameMethyldopa
Accession NumberDB00968  (APRD01106)
Typesmall molecule
Groupsapproved
Description

An alpha-2 adrenergic agonist that has both central and peripheral nervous system effects. Its primary clinical use is as an antihypertensive agent. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
(S)-(-)-alpha-MethyldopaNot AvailableNot Available
3-Hydroxy-alpha-methyl-L-tyrosineNot AvailableNot Available
Alpha medopaNot AvailableNot Available
alpha-Methyl dopaNot AvailableNot Available
AlphamethyldopaNot AvailableNot Available
AMDNot AvailableNot Available
L-alpha-MethyldopaNot AvailableNot Available
L-Methyl DopaNot AvailableNot Available
α-methyl-L-dopaNot AvailableNot Available
Salts
Name/CAS Structure Properties
Methyldopa sesquihydrate
Thumb Not applicable DBSALT000988
Brand names
NameCompany
AldometNot Available
AldometilNot Available
AldominNot Available
DopametNot Available
HypolagNot Available
MedometNot Available
MedoprenNot Available
NovomedopaNot Available
Nu-MedopaNot Available
Brand mixtures
Brand NameIngredients
AldoclorChlorothiazide + Methyldopa
AldorilHydrochlorothiazide + Methyldopa
Apo MethazideHydrochlorothiazide + Methyldopa
Novo-DoparilHydrochlorothiazide + Methyldopa
PMS-DopazideHydrochlorothiazide + Methyldopa
SupresChlorothiazide + Methyldopa
Categories
CAS number555-30-6
WeightAverage: 211.2145
Monoisotopic: 211.084457909
Chemical FormulaC10H13NO4
InChI KeyInChIKey=CJCSPKMFHVPWAR-UEQNJFAPNA-N
InChI
InChI=1/C10H13NO4/c1-10(11,9(14)15)5-6-2-3-7(12)8(13)4-6/h2-4,12-13H,5,11H2,1H3,(H,14,15)/t10-/s2
IUPAC Name
(2S)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid
SMILES
C[C@](N)(CC1=CC=C(O)C(O)=C1)C(O)=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassPhenols and Derivatives
Direct parentCatecholamines and Derivatives
Alternative parentsPhenylpropanoic Acids; Alpha Amino Acids and Derivatives; Amphetamines and Derivatives; Amino Fatty Acids; Polyols; Enolates; Carboxylic Acids; Polyamines; Enols; Monoalkylamines
Substituentspolyol; carboxylic acid; enolate; enol; polyamine; carboxylic acid derivative; amine; primary amine; primary aliphatic amine; organonitrogen compound
Classification descriptionThis compound belongs to the catecholamines and derivatives. These are compounds containing 4-(2-Aminoethyl)pyrocatechol [4-(2-aminoethyl)benzene-1,2-diol] or a derivative thereof formed by substitution.
Pharmacology
IndicationFor use in the treatment of hypertension.
PharmacodynamicsMethyldopa is an aromatic-amino-acid decarboxylase inhibitor in animals and in man. Only methyldopa, the L-isomer of alpha-methyldopa, has the ability to inhibit dopa decarboxylase and to deplete animal tissues of norepinephrine. In man the antihypertensive activity appears to be due solely to the L-isomer. About twice the dose of the racemate (DL-alpha-methyldopa) is required for equal antihypertensive effect. Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Cardiac output usually is maintained without cardiac acceleration. In some patients the heart rate is slowed. Normal or elevated plasma renin activity may decrease in the course of methyldopa therapy. Methyldopa reduces both supine and standing blood pressure. Methyldopa usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.
Mechanism of actionAlthough the mechanism of action has yet to be conclusively demonstrated, the resultant hypotensive effect is most likely due to the drug's action on the CNS. Methyldopa is converted into the metabolite, alpha-methylnorepinephrine, in the CNS, where it stimulates the central inhibitory alpha-adrenergic receptors, leading to a reduction in sympathetic tone, total peripheral resistance, and blood pressure. Reduction in plasma renin activity, as well as the inhibition of both central and peripheral norepinephrine and serotonine production may also contribute to the drug's antihypertensive effect, although this is not a major mechanism of action. This is done through the inhibition of the decarboxylation of dihydroxyphenylalanine (dopa)—the precursor of norepinephrine—and of 5-hydroxytryptophan (5-HTP)—the precursor of serotonin—in the CNS and in most peripheral tissues.
AbsorptionAbsorption from the gastrointestinal tract is variable but averages approximately 50%.
Volume of distributionNot Available
Protein bindingLow (less than 20%).
Metabolism

Hepatic, extensively metabolized. The known urinary metabolites are: a-methyldopa mono-0-sulfate; 3-0-methyl-a-methyldopa; 3,4-dihydroxyphenylacetone; a-methyldopamine; 3-0-methyl-a-methyldopamine and their conjugates.

SubstrateEnzymesProduct
Methyldopa
    3-O-methyl-a-methyldopaDetails
    Methyldopa
      3-O-methyl-a-methyldopamineDetails
      Methyldopa
        a-methyldopa mono-0-sulfateDetails
        Methyldopa
          a-methyldopamineDetails
          Route of eliminationMethyldopa is extensively metabolized. The known urinary metabolites are: α-methyldopa mono-O-sulfate; 3-0-methyl-α-methyldopa; 3,4-dihydroxyphenylacetone; α-methyldopamine; 3-0-methyl-α-methyldopamine and their conjugates. Approximately 70 percent of the drug which is absorbed is excreted in the urine as methyldopa and its mono-O-sulfate conjugate. Methyldopa crosses the placental barrier, appears in cord blood, and appears in breast milk.
          Half lifeThe plasma half-life of methyldopa is 105 minutes.
          Clearance
          • Renal cl=130 mL/min [healthy]
          ToxicityThe oral LD50 of methyldopa is greater than 1.5 g/kg in both the mouse and the rat. Symptoms of overdose include bloating, constipation, diarrhea, dizziness, extreme drowsiness, gas, light-headedness, nausea, severely low blood pressure, slow heartbeat, vomiting, and weakness.
          Affected organisms
          • Humans and other mammals
          PathwaysNot Available
          SNP Mediated EffectsNot Available
          SNP Mediated Adverse Drug ReactionsNot Available
          ADMET
          Predicted ADMET features
          Property Value Probability
          Human Intestinal Absorption + 0.9374
          Blood Brain Barrier - 0.9276
          Caco-2 permeable - 0.8957
          P-glycoprotein substrate Substrate 0.6066
          P-glycoprotein inhibitor I Non-inhibitor 0.9852
          P-glycoprotein inhibitor II Non-inhibitor 0.9895
          Renal organic cation transporter Non-inhibitor 0.9357
          CYP450 2C9 substrate Non-substrate 0.7757
          CYP450 2D6 substrate Non-substrate 0.8
          CYP450 3A4 substrate Non-substrate 0.6053
          CYP450 1A2 substrate Non-inhibitor 0.9045
          CYP450 2C9 substrate Non-inhibitor 0.9369
          CYP450 2D6 substrate Non-inhibitor 0.9491
          CYP450 2C19 substrate Non-inhibitor 0.9233
          CYP450 3A4 substrate Non-inhibitor 0.864
          CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9551
          Ames test Non AMES toxic 0.8185
          Carcinogenicity Non-carcinogens 0.8997
          Biodegradation Not ready biodegradable 0.8077
          Rat acute toxicity 1.6281 LD50, mol/kg Not applicable
          hERG inhibition (predictor I) Weak inhibitor 0.9939
          hERG inhibition (predictor II) Non-inhibitor 0.9629
          Pharmacoeconomics
          Manufacturers
          • Merck and co inc
          • Merck research laboratories div merck co inc
          • Accord health care inc
          • Duramed pharmaceuticals inc sub barr laboratories inc
          • Halsey drug co inc
          • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
          • Mutual pharmaceutical co inc
          • Mylan pharmaceuticals inc
          • Par pharmaceutical inc
          • Parke davis div warner lambert co
          • Pliva inc
          • Purepac pharmaceutical co
          • Roxane laboratories inc
          • Sandoz inc
          • Superpharm corp
          • Teva pharmaceuticals usa inc
          • Watson laboratories inc
          • Abraxis pharmaceutical products
          • Baxter healthcare corp anesthesia and critical care
          • Hospira inc
          • Luitpold pharmaceuticals inc
          • Marsam pharmaceuticals llc
          • Smith and nephew solopak div smith and nephew
          • Teva parenteral medicines inc
          Packagers
          Dosage forms
          FormRouteStrength
          TabletOral
          Prices
          Unit descriptionCostUnit
          Aldoclor 250-250 mg tablet0.67USDtablet
          Methyldopa 500 mg tablet0.67USDtablet
          Methyldopa 250 mg tablet0.39USDtablet
          Apo-Methyldopa 500 mg Tablet0.27USDtablet
          Methyldopate 250 mg/5 ml vial0.24USDml
          Apo-Methyldopa 250 mg Tablet0.15USDtablet
          Apo-Methyldopa 125 mg Tablet0.1USDtablet
          DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
          PatentsNot Available
          Properties
          Statesolid
          Experimental Properties
          PropertyValueSource
          melting point300 dec °CPhysProp
          water solubility1E+004 mg/L (at 25 °C)MERCK INDEX (1996)
          logP-1.7Not Available
          Predicted Properties
          PropertyValueSource
          water solubility2.26e+00 g/lALOGPS
          logP-2ALOGPS
          logP-1.4ChemAxon
          logS-2ALOGPS
          pKa (strongest acidic)1.73ChemAxon
          pKa (strongest basic)9.85ChemAxon
          physiological charge0ChemAxon
          hydrogen acceptor count5ChemAxon
          hydrogen donor count4ChemAxon
          polar surface area103.78ChemAxon
          rotatable bond count3ChemAxon
          refractivity53.79ChemAxon
          polarizability20.73ChemAxon
          number of rings1ChemAxon
          bioavailability1ChemAxon
          rule of fiveYesChemAxon
          Ghose filterNoChemAxon
          Veber's ruleNoChemAxon
          MDDR-like ruleNoChemAxon
          Spectra
          SpectraNot Available
          References
          Synthesis Reference

          DrugSyn.org

          US2868818
          General Reference
          1. Mah GT, Tejani AM, Musini VM: Methyldopa for primary hypertension. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD003893. Pubmed
          2. McCoy S, Baldwin K: Pharmacotherapeutic options for the treatment of preeclampsia. Am J Health Syst Pharm. 2009 Feb 15;66(4):337-44. Pubmed
          3. Sica DA: Centrally acting antihypertensive agents: an update. J Clin Hypertens (Greenwich). 2007 May;9(5):399-405. Pubmed
          4. van Zwieten PA: Development and trends in the drug treatment of essential hypertension. J Hypertens Suppl. 1992 Dec;10(7):S1-12. Pubmed
          5. Rosenthal T, Oparil S: The effect of antihypertensive drugs on the fetus. J Hum Hypertens. 2002 May;16(5):293-8. Pubmed
          6. van Zwieten PA, Timmermans PB: Pharmacology and characterization of central alpha-adrenoceptors involved in the effect of centrally acting antihypertensive drugs. Chest. 1983 Feb;83(2 Suppl):340-3. Pubmed
          7. van Zwieten PA: Pharmacology of centrally acting hypotensive drugs. Br J Clin Pharmacol. 1980;10 Suppl 1:13S-20S. Pubmed
          External Links
          ResourceLink
          KEGG DrugD08205
          KEGG CompoundC07194
          ChEBI61058
          ChEMBLCHEMBL459
          Therapeutic Targets DatabaseDAP000226
          PharmGKBPA450453
          Drug Product Database426830
          RxListhttp://www.rxlist.com/cgi/generic2/methyl.htm
          Drugs.comhttp://www.drugs.com/cdi/methyldopa.html
          PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/ald1012.shtml
          WikipediaMethyldopa
          ATC CodesC02AB01C02AB02
          AHFS Codes
          • 24:08.16
          PDB EntriesNot Available
          FDA labelshow(155 KB)
          MSDSshow(53.4 KB)
          Interactions
          Drug Interactions
          Drug
          CarteololPossible hypertensive crisis
          DobutamineIncreased arterial pressure
          DopamineIncreased arterial pressure
          EntacaponeEntacapone may increase the effect and toxicity of the sympathomimetic, methyldopa.
          EphedraIncreased arterial pressure
          EphedrineIncreased arterial pressure
          EpinephrineIncreased arterial pressure
          FenoterolIncreased arterial pressure
          HaloperidolMethyldopa increases haloperidol effect or risk of psychosis
          IronIron decreases the absorption of dopa derivatives
          Iron DextranIron decreases the absorption of dopa derivatives
          IsoprenalineIncreased arterial pressure
          L-DOPAMethyldopa increases the effect and toxicity of levodopa
          LithiumMethyldopa may increase the adverse effects of lithium without affecting lithium serum levels. Monitor for signs and symptoms of lithium toxicity during concomitant therapy.
          MephentermineIncreased arterial pressure
          MetaraminolIncreased arterial pressure
          MethoxamineIncreased arterial pressure
          NadololPossible hypertensive crisis
          NorepinephrineIncreased arterial pressure
          OrciprenalineIncreased arterial pressure
          OxprenololPossible hypertensive crisis
          PenbutololPossible hypertensive crisis
          PhenylephrineIncreased arterial pressure
          PhenylpropanolamineIncreased arterial pressure
          PindololPossible hypertensive crisis
          PirbuterolIncreased arterial pressure
          ProcaterolIncreased arterial pressure
          PropranololPossible hypertensive crisis
          PseudoephedrineIncreased arterial pressure
          SalbutamolIncreased arterial pressure
          SotalolPossible hypertensive crisis
          TerbutalineIncreased arterial pressure
          TimololPossible hypertensive crisis
          TranylcypromineThe MAO inhibitor, Tranylcypromine, may increase the adverse effects of Methyldopa. Concomitant therapy is contraindicated.
          Food Interactions
          • Avoid alcohol.
          • Avoid natural licorice.
          • Increase dietary intake of magnesium, folate, vitamin B6, B12, and/or consider taking a multivitamin.
          • May take Vitamin D.
          • No iron, zinc or fluoride within 2 hours of taking this medication.
          • Take without regard to meals.

          1. Alpha-2A adrenergic receptor

          Kind: protein

          Organism: Human

          Pharmacological action: yes

          Components

          Name UniProt ID Details
          Alpha-2A adrenergic receptor P08913 Details

          References:

          1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
          2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
          3. Sica DA: Centrally acting antihypertensive agents: an update. J Clin Hypertens (Greenwich). 2007 May;9(5):399-405. Pubmed
          4. Kawasaki H: [Centrally acting sympathetic inhibitors for therapy of patients with hypertension] Nippon Rinsho. 1997 Aug;55(8):2081-5. Pubmed
          5. Head GA: Central imidazoline- and alpha 2-receptors involved in the cardiovascular actions of centrally acting antihypertensive agents. Ann N Y Acad Sci. 1999 Jun 21;881:279-86. Pubmed
          6. van Zwieten PA: New central mediators as targets of centrally acting antihypertensive drugs. Clin Exp Hypertens. 1996 Apr-May;18(3-4):291-303. Pubmed
          7. van Zwieten PA: Development and trends in the drug treatment of essential hypertension. J Hypertens Suppl. 1992 Dec;10(7):S1-12. Pubmed
          8. Velliquette RA, Ernsberger P: Contrasting metabolic effects of antihypertensive agents. J Pharmacol Exp Ther. 2003 Dec;307(3):1104-11. Epub 2003 Oct 13. Pubmed

          1. Catechol O-methyltransferase

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: substrate

          Components

          Name UniProt ID Details
          Catechol O-methyltransferase P21964 Details

          References:

          1. Alazizi A, Liu MY, Williams FE, Kurogi K, Sakakibara Y, Suiko M, Liu MC: Identification, characterization, and ontogenic study of a catechol O-methyltransferase from zebrafish. Aquat Toxicol. 2011 Mar;102(1-2):18-23. Epub 2010 Dec 29. Pubmed
          2. Ameyaw MM, Syvanen AC, Ulmanen I, Ofori-Adjei D, McLeod HL: Pharmacogenetics of catechol-O-methyltransferase: frequency of low activity allele in a Ghanaian population. Hum Mutat. 2000 Nov;16(5):445-6. Pubmed

          1. Solute carrier family 15 member 1

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: inhibitor

          Components

          Name UniProt ID Details
          Solute carrier family 15 member 1 P46059 Details

          References:

          1. Han HK, Rhie JK, Oh DM, Saito G, Hsu CP, Stewart BH, Amidon GL: CHO/hPEPT1 cells overexpressing the human peptide transporter (hPEPT1) as an alternative in vitro model for peptidomimetic drugs. J Pharm Sci. 1999 Mar;88(3):347-50. Pubmed

          Comments
          Drug created on June 13, 2005 07:24 / Updated on January 12, 2014 21:19