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Identification
Name Methyldopa
Accession Number DB00968 (APRD01106)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Alpha medopa
  • Alphamethyldopa
  • AMD
  • L-Methyl Dopa
  • Methyldopa anhydrous
  • Methyldopate
  • Methyldopate HCL
  • Mk. b51
Brand names
  • Aldoclor-150
  • Aldoclor-250
  • Aldomet
  • Aldometil
  • Aldomin
  • Aldoril 15
  • Aldoril 25
  • Aldoril D30
  • Aldoril D50
  • Apo-Methyldopa
  • Bayer 1440 L
  • Baypresol
  • Becanta
  • Dopamet
  • Dopamethyperpax
  • Dopatec
  • Dopegyt
  • Grospisk
  • Hyperpax
  • Hypolag
  • Medomet
  • Medopa
  • Medopal
  • Medopren
  • Methoplain
  • Novomedopa
  • Nu-Medopa
  • Presinol
  • Presolisin
  • Sedometil
  • Sembrina
Brand name mixtures
  • Aldoril 15 Tab (Hydrochlorothiazide + Methyldopa)
  • Aldoril 25 Tab (Hydrochlorothiazide + Methyldopa)
  • Apo Methazide 15 (Hydrochlorothiazide + Methyldopa)
  • Apo Methazide 25 (Hydrochlorothiazide + Methyldopa)
  • Novo-Doparil 15 Tab (Hydrochlorothiazide + Methyldopa)
  • Novo-Doparil 25 Tab (Hydrochlorothiazide + Methyldopa)
  • Pms-Dopazide 15 Tab (Hydrochlorothiazide + Methyldopa)
  • Pms-Dopazide-25 Tab (Hydrochlorothiazide + Methyldopa)
  • Supres 150 Tab (Chlorothiazide + Methyldopa)
  • Supres 250 Tab (Chlorothiazide + Methyldopa)
Categories
  • Antihypertensive Agents
  • Sympatholytics
  • Adrenergic alpha-Agonists
CAS number 555-30-6
Weight Average: 211.2145
Monoisotopic: 211.084457909
Chemical Formula C10H13NO4
InChI Key InChIKey=CJCSPKMFHVPWAR-JTQLQIEISA-N
InChI
InChI=1S/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-/m0/s1
Plain Text
IUPAC Name
(2S)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid
SMILES
C[C@](N)(CC1=CC(O)=C(O)C=C1)C(O)=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenols and Derivatives
  • Amino Acids
  • Amphetamines
  • Catecholamines and Derivatives
Substructures
  • Hydroxy Compounds
  • Phenols and Derivatives
  • Acetates
  • Aliphatic and Aryl Amines
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Catechols
  • Phenethylamines
  • Aromatic compounds
  • Amino Acids
  • Phenyl Esters
  • Amphetamines
  • Catecholamines and Derivatives
Pharmacology
Indication For use in the treatment of hypertension.
Pharmacodynamics Methyldopa is an aromatic-amino-acid decarboxylase inhibitor in animals and in man. Only methyldopa, the L-isomer of alpha-methyldopa, has the ability to inhibit dopa decarboxylase and to deplete animal tissues of norepinephrine. In man the antihypertensive activity appears to be due solely to the L-isomer. About twice the dose of the racemate (DL-alpha-methyldopa) is required for equal antihypertensive effect. Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Cardiac output usually is maintained without cardiac acceleration. In some patients the heart rate is slowed. Normal or elevated plasma renin activity may decrease in the course of methyldopa therapy. Methyldopa reduces both supine and standing blood pressure. Methyldopa usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.
Mechanism of action Although the mechanism of action has yet to be conclusively demonstrated, the resultant hypotensive effect is most likely due to the drug's action on the CNS. Methyldopa is converted into the metabolite, alpha-methylnorepinephrine, in the CNS, where it stimulates the central inhibitory alpha-adrenergic receptors, leading to a reduction in sympathetic tone, total peripheral resistance, and blood pressure. Reduction in plasma renin activity, as well as the inhibition of both central and peripheral norepinephrine and serotonine production may also contribute to the drug's antihypertensive effect, although this is not a major mechanism of action. This is done through the inhibition of the decarboxylation of dihydroxyphenylalanine (dopa)—the precursor of norepinephrine—and of 5-hydroxytryptophan (5-HTP)—the precursor of serotonin—in the CNS and in most peripheral tissues.
Absorption Absorption from the gastrointestinal tract is variable but averages approximately 50%.
Volume of distribution Not Available
Protein binding Low (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.

Enzyme Metabolite Reaction Km Vmax
Catechol O-methyltransferase O-methylation
Route of elimination Methyldopa is extensively metabolized. The known urinary metabolites are: α-methyldopa mono-O-sulfate; 3-0-methyl-α-methyldopa; 3,4-dihydroxyphenylacetone; α-methyldopamine; 3-0-methyl-α-methyldopamine and their conjugates. Approximately 70 percent of the drug which is absorbed is excreted in the urine as methyldopa and its mono-O-sulfate conjugate. Methyldopa crosses the placental barrier, appears in cord blood, and appears in breast milk.
Half life The plasma half-life of methyldopa is 105 minutes.
Clearance
  • Renal cl=130 mL/min [healthy]
Toxicity The oral LD50 of methyldopa is greater than 1.5 g/kg in both the mouse and the rat. Symptoms of overdose include bloating, constipation, diarrhea, dizziness, extreme drowsiness, gas, light-headedness, nausea, severely low blood pressure, slow heartbeat, vomiting, and weakness.
Affected organisms
  • Humans and other mammals
Pathways Not Available
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
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Aldoclor 250-250 mg tablet 0.67 USD tablet
Methyldopa 500 mg tablet 0.67 USD tablet
Methyldopa 250 mg tablet 0.39 USD tablet
Apo-Methyldopa 500 mg Tablet 0.27 USD tablet
Methyldopate 250 mg/5 ml vial 0.24 USD ml
Apo-Methyldopa 250 mg Tablet 0.15 USD tablet
Apo-Methyldopa 125 mg Tablet 0.1 USD tablet
Patents Not Available
Properties
State solid
Melting point 300 oC
Experimental Properties
Property Value Source
water solubility 1000 mg/L PhysProp
logP -1.7 PhysProp
Predicted Properties
Property Value Source
water solubility 2.26e+00 g/l ALOGPS
logP -2.02 ALOGPS
logP -1.50 ChemAxon Molconvert
logS -1.97 ALOGPS
pKa 9.14 ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 4 ChemAxon Molconvert
polar surface area 103.78 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 53.79 ChemAxon Molconvert
polarizability 20.79 ChemAxon Molconvert
References
Synthesis Reference Not Available
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
Resource Link
KEGG Compound C07194 Link_out
PubChem Compound 38853 Link_out
PubChem Substance 46508535 Link_out
ChemSpider 35562 Link_out
ChEBI 61058 Link_out
ChEMBL 61058 Link_out
Therapeutic Targets Database DAP000226 Link_out
PharmGKB PA450453 Link_out
Drug Product Database 426830 Link_out
RxList http://www.rxlist.com/cgi/generic2/methyl.htm Link_out
Drugs.com http://www.drugs.com/cdi/methyldopa.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/ald1012.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Methyldopa Link_out
ATC Codes
  • C02AB01
  • C02AB02
AHFS Codes
  • 24:08.16
PDB Entries Not Available
FDA label show (155.5 KB)
MSDS show (53.4 KB)
Interactions
Drug Interactions Not Available
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

Pharmacological action: yes

Alpha-2 adrenergic receptors mediate the catecholamine- induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazoline > clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, the rank order is yohimbine > phentolamine = mianserine > chlorpromazine = spiperone = prazosin > propanolol > alprenolol = pindolol

Organism class: human
UniProt ID: P08913 Link_out
Gene: ADRA2A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Enzymes

1. Catechol O-methyltransferase

Actions: substrate

Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol

UniProt ID: P21964 Link_out
Gene: COMT Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Oligopeptide transporter, small intestine isoform

Actions: inhibitor

Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. May constitute a major route for the absorption of protein digestion end-products

UniProt ID: P46059 Link_out
Gene: SLC15A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 August 18, 2011 10:17

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.