Methyldopa

{{Short description|Medication used to treat high blood pressure}} {{Drugbox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 462251064 | IUPAC_name = (''S'')-2-amino-3-(3,4-dihydroxyphenyl)-2-methyl-propanoic acid | image = Methyldopa.svg | image_class = skin-invert-image | alt = Skeletal formula of methyldopa | image2 = Methyldopa molecule ball.png | image_class2 = bg-transparent | alt2 = Ball-and-stick model of the methyldopa molecule

| tradename = Aldomet, Aldoril, Dopamet, others | Drugs.com = {{drugs.com|monograph|methyldopa}} | MedlinePlus = a682242 | DailyMedID = Methyldopa | pregnancy_AU = A | legal_AU = S4 | legal_CA = Rx-only | legal_UK = POM | legal_US = Rx-only | routes_of_administration = By mouth, intravenous

| index_label = | index2_label = anhydrous | CAS_number2_Ref = {{cascite|correct|CAS}} | CAS_number2 = 555-30-6 | UNII2_Ref = {{fdacite|correct|FDA}} | UNII2 = M4R0H12F6M | IUPHAR_ligand = 5217 | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 41372-08-1 | ATC_prefix = C02 | ATC_suffix = AB01 | ATC_supplemental = {{ATC|C02|AB02}} (racemic) | PubChem2 = 40175 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00968 | KEGG = D00405 | PubChem = 38853 | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID = 35562 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 56LH93261Y | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 459 | synonyms = α-Methyl-L-DOPA; α-Methyl-levodopa; α-Methyl-DOPA; L-α-Methyl-3,4-dihydroxyphenylalanine

| C = 10 | H = 13 | N = 1 | O = 4 | smiles = C[C@](N)(Cc1ccc(O)c(O)c1)C(=O)O | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | StdInChI = 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 | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} | StdInChIKey = CJCSPKMFHVPWAR-JTQLQIEISA-N }}

'''Methyldopa''', also known as '''α-methyl-L-DOPA''' and sold under the brand name '''Aldomet''' among others, is a medication used for high blood pressure.<ref name="AHFS2016" /> It is one of the preferred treatments for high blood pressure in pregnancy.<ref name="AHFS2016" /> For other types of high blood pressure including very high blood pressure resulting in symptoms other medications are typically preferred.<ref name="AHFS2016" /> It can be given by mouth or injection into a vein.<ref name=AHFS2016/> Onset of effects is around 5 hours and they last about a day.<ref name="AHFS2016">{{cite web|title=Methyldopa|url=https://www.drugs.com/monograph/methyldopa.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221010844/https://www.drugs.com/monograph/methyldopa.html|archive-date=21 December 2016}}</ref>

Common side effects include sleepiness.<ref name=AHFS2016/> More severe side effects include red blood cell breakdown, liver problems, and allergic reactions.<ref name=AHFS2016/> Methyldopa is in the alpha-2 adrenergic receptor agonist family of medication. It works by stimulating the brain to decrease the activity of the sympathetic nervous system.<ref name=AHFS2016/>

Methyldopa was discovered in 1960.<ref name=Wal2012>{{cite book| vauthors = Walker RS |title=Trends and Changes in Drug Research and Development|date=2012|publisher=Springer Science & Business Media|isbn=978-94-009-2659-2|page=109|url=https://books.google.com/books?id=FB_2CAAAQBAJ&pg=PA109|language=en|url-status=live|archive-url=https://web.archive.org/web/20160914021552/https://books.google.ca/books?id=FB_2CAAAQBAJ&pg=PA109|archive-date=2016-09-14}}</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref>

== Medical uses == Methyldopa is used in the clinical treatment of the following disorders: * Hypertension (or high blood pressure) * Gestational hypertension (or pregnancy-induced hypertension) and pre-eclampsia.<ref>{{Cite book| vauthors = Malha L, Podymow T, August P |chapter-url=https://www.sciencedirect.com/science/article/pii/B9780323429733000391|title=Hypertension: A Companion to Braunwald's Heart Disease|publisher=Elsevier|year=2018|isbn=978-0-323-42973-3|edition=3rd|pages=361–373|language=en|chapter=39 - Hypertension in Pregnancy|doi=10.1016/B978-0-323-42973-3.00039-1}}</ref>

== Side effects == Methyldopa is capable of inducing a number of adverse side effects, which range from mild to severe. Nevertheless, they are generally mild when the dose is less than 1 gram per day.<ref>{{cite book |author1=Bnf |title=British National Formulary 56 |date=September 2008 |pages=[https://archive.org/details/britishnationalf0000unse_k4e9/page/95 95–96] |isbn=978-0-85369-778-7 }}</ref> Side effects may include:

* Psychological{{Citation needed|date=February 2025}} ** Depression ** Suicidal ideation ** Nightmares ** Apathy, anhedonia, or dysphoria ** Anxiety, especially social anxiety ** Decreased alertness, awareness, and wakefulness ** Impaired attention and concentration ** Fatigue ** Malaise ** Drowsiness ** Restlessness ** Cognitive and memory impairment ** Derealization or depersonalization, as well as mild psychosis ** Sexual dysfunction including impaired libido, desire, and drive * Physiological{{Citation needed|date=February 2025}} ** Dizziness, lightheadedness, or vertigo ** Miosis or pupil constriction ** Xerostomia or dry mouth ** Gastrointestinal disturbances such as diarrhea or constipation ** Headache or migraine ** Myalgia or muscle aches, arthralgia or joint pain, or paresthesia ("pins and needles") ** Restless legs syndrome (RLS) ** Parkinsonian symptoms such as muscle tremors, rigidity, hypokinesia, or balance or postural instability ** Akathisia, ataxia, dyskinesia, as well as even tardive dyskinesia or dystonia ** Bell's palsy or facial paralysis ** Sexual dysfunction ** Hyperprolactinemia *** Gynecomastia in males, amenorrhoea or absence of menstrual cycles in females ** Bradycardia ** Hypotension ** Orthostatic hypotension ** Hepatitis, hepatotoxicity, or liver dysfunction or damage ** Pancreatitis ** Warm autoimmune hemolytic anemia or deficiency in red blood cells (RBCs) ** Myelotoxicity or bone marrow suppression, potentially leading to thrombocytopenia, blood platelet deficiency, leukopenia, or white blood cell deficiency ** Hypersensitivity (e.g., lupus erythematosus, myocarditis, or pericarditis) ** Lichenoid reactions (e.g., skin lesions or rashes) ** Pallor

=== Withdrawal === Rebound hypertension via withdrawal on account of tolerance upon the abrupt discontinuation of methyldopa has been reported.<ref>[http://www.inchem.org/documents/pims/pharm/methyldo.htm Methyldopa (PIM 342)] {{webarchive|url=https://web.archive.org/web/20080313130358/http://www.inchem.org/documents/pims/pharm/methyldo.htm |date=2008-03-13 }}</ref>

== Mechanism of action == The mechanism of action of methyldopa is not fully clear. It may reduce the dopaminergic and serotonergic transmission in the central and peripheral nervous system and it indirectly affects norepinephrine (noradrenaline) synthesis by way of inhibiting dopamine synthesis. Methyldopa acts on alpha-2 adrenergic receptors, which are found on the pre synaptic nerve terminal.<ref name="AHFS2016" /> This inhibits the release of norepinephrine from the presynaptic neuron.

The S-enantiomer of methyldopa is a competitive inhibitor of the enzyme aromatic L-amino acid decarboxylase (LAAD), which converts L-DOPA into dopamine. L-DOPA can cross the blood–brain barrier and thus methyldopa may have similar effects. LAAD converts it into alpha-methyldopamine, a false precursor to norepinephrine, which in turn reduces synthesis of norepinephrine in the vesicles. Dopamine beta hydroxylase (DBH) converts alpha-methyldopamine into alpha-methylnorepinephrine, which is an agonist of the presynaptic α2-adrenergic receptor causing inhibition of neurotransmitter release.

Methyldopa has been found to be a monoamine depleting agent.<ref name="TungGoldbergHollister1988">{{cite journal | vauthors = Tung CS, Goldberg MR, Hollister AS, Sweetman BJ, Robertson D | title = Depletion of brainstem epinephrine stores by alpha-methyldopa: possible relation to attenuated sympathetic outflow | journal = Life Sci | volume = 42 | issue = 23 | pages = 2365–2371 | date = 1988 | pmid = 3287081 | doi = 10.1016/0024-3205(88)90190-7 | url = }}</ref>

== Pharmacokinetics == Maximum decrease in blood pressure occurs 4–6 hours after oral dosage. The half-life of methyldopa is 105 minutes.<ref>{{Cite web |title=DailyMed - METHYLDOPA tablet, film coated |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=00206aae-7db1-4ae9-8500-b03fd6788d74 |access-date=2022-07-25 |website=dailymed.nlm.nih.gov}}</ref> Methyldopa exhibits variable absorption from the gastrointestinal tract. It is metabolized in the liver and intestines and is excreted in urine.{{Citation needed|date=February 2025}}

== History == When methyldopa was first introduced, it was the mainstay of antihypertensive treatment, but its use has declined on account of relatively severe adverse side effects, with increased use of other safer and more tolerable agents such as alpha blockers, beta blockers, and calcium channel blockers. Additionally, it has yet to be associated with reducing adverse cardiovascular events including myocardial infarction and stroke, or overall all-cause mortality reduction in clinical trials.<ref name="pmid19821316">{{cite journal | vauthors = Mah GT, Tejani AM, Musini VM | title = Methyldopa for primary hypertension | journal = The Cochrane Database of Systematic Reviews | volume = 2009 | issue = 4 | article-number = CD003893 | date = October 2009 | pmid = 19821316 | pmc = 7154320 | doi = 10.1002/14651858.CD003893.pub3 }}</ref> Nonetheless, one of methyldopa's still current indications is in the management of pregnancy-induced hypertension (PIH), as it is relatively safe in pregnancy compared to many other antihypertensives which may affect the fetus.{{Citation needed|date=February 2025}}

== See also == * Difluoromethyldopa * D-DOPA (dextrodopa) * L-DOPA (levodopa; trade names Sinemet, Pharmacopa, Atamet, Stalevo, Madopar, Prolopa, etc.) * L-DOPS (droxidopa) * Dopamine (Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc.) * Norepinephrine (noradrenaline; Levophed, etc.) * Epinephrine (adrenaline; Adrenalin, EpiPed, Twinject, etc.) * [https://www.chemdrug.com/article/8/3284/16419452.html MK-872] HCl salt: [55943-64-1] * α-Methyltyrosine * α-Methyl-5-hydroxytryptophan

== References == {{Reflist}}

== External links == {{Commons category|Methyldopa}}

{{Antihypertensives and diuretics}} {{Antiparkinson}} {{Adrenergic receptor modulators}} {{Monoamine metabolism modulators}} {{Phenethylamines}} {{portal bar|Medicine}}

Category:Catecholamines Category:Aromatic L-amino acid decarboxylase inhibitors Category:Alpha1-adrenergic agonists Category:Alpha2-adrenergic agonists Category:Antihypertensive agents Category:Beta-adrenergic agonists Category:Hepatotoxins Category:World Health Organization essential medicines Category:Wikipedia medicine articles ready to translate