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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 KeyCJCSPKMFHVPWAR-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
Not Available
3-O-methyl-a-methyldopaDetails
Methyldopa
Not Available
3-O-methyl-a-methyldopamineDetails
Methyldopa
Not Available
a-methyldopa mono-0-sulfateDetails
Methyldopa
Not Available
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.

Targets

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

2. Aromatic-L-amino-acid decarboxylase

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Aromatic-L-amino-acid decarboxylase P20711 Details

References:

  1. SOURKES TL: Inhibition of dihydroxy-phenylalanine decarboxylase by derivatives of phenylalanine. Arch Biochem Biophys. 1954 Aug;51(2):444-56. Pubmed

Enzymes

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

Transporters

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

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