Midodrine

{{Short description|Antihypotensive medication}} {{Use dmy dates|date=August 2021}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | image = Midodrine structure.svg | image_class = skin-invert-image | width = 250px | caption = Above: molecular structure of midodrine Below: 3D representation of midodrine | image2 = Midodrine 3D.png | image_class2 = bg-transparent | width2 = 250px

| pronounce = | tradename = Proamatine, others | Drugs.com = {{drugs.com|monograph|midodrine-hydrochloride}} | MedlinePlus = a616030 | DailyMedID = Midodrine | pregnancy_AU = C | pregnancy_AU_comment = | pregnancy_category = | routes_of_administration = By mouth | class = α1-Adrenergic receptor agonist; Antihypotensive agent | ATC_prefix = C01 | ATC_suffix = CA17 | ATC_supplemental =

| legal_AU = S4 | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA =  | legal_CA_comment = | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK =  | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Proamatine FDA label">{{cite web | title=Proamatine- midodrine hydrochloride tablet | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9e8874f0-ad2e-41ce-8a35-bed819615a5d | access-date=14 August 2021}}</ref> | legal_EU = | legal_EU_comment = | legal_UN =  | legal_UN_comment = | legal_status =

| bioavailability = 93% (as desglymidodrine)<ref name="Proamatine FDA label" /><ref name="Gilden2004">{{cite book | vauthors = Gilden JL | title=Primer on the Autonomic Nervous System | chapter=Midodrine and Other Sympathomimetics | publisher=Elsevier | date=2004 | isbn=978-0-12-589762-4 | doi=10.1016/b978-012589762-4/50113-4 | pages=413–415}}</ref> | protein_bound = | metabolism = Deglycination<ref name="Proamatine FDA label" /><ref name="Gilden2004" /> | metabolites = • Desglymidodrine<ref name="Proamatine FDA label" /><ref name="Gilden2004" /> | onset = ≤1 hour<ref name="Proamatine FDA label" /> | elimination_half-life = Midodrine: 0.5{{nbsp}}hours<ref name="Gilden2004" /> Desglymidodrine: 2–4{{nbsp}}hours<ref name="Gilden2004" /> | duration_of_action = 2–6{{nbsp}}hours<ref name="Proamatine FDA label" /><ref name="Gilden2004" /> | excretion =

| CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 42794-76-3 | CAS_supplemental = | PubChem = 4195 | IUPHAR_ligand = 7240 | DrugBank = DB00211 | ChemSpiderID = 4050 | UNII = 6YE7PBM15H | KEGG = D08220 | ChEBI = 6933 | ChEMBL = 1201212 | NIAID_ChemDB = | PDB_ligand = | synonyms = ST-1085; TS-701; 3,6-Dimethoxy-β-hydroxy-''N''-aminoethanonyl-2-phenylethylamine; 2-Amino-''N''-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide; 1-2',5'-Dimethoxyphenyl-1)-2 glycinamidoethanol

| IUPAC_name = (''RS'')-''N''-[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]glycinamide | C = 12 | H = 18 | N = 2 | O = 4 | chirality = Racemic mixture | SMILES = O=C(NCC(O)c1cc(OC)ccc1OC)CN | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C12H18N2O4/c1-17-8-3-4-11(18-2)9(5-8)10(15)7-14-12(16)6-13/h3-5,10,15H,6-7,13H2,1-2H3,(H,14,16) | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = PTKSEFOSCHHMPD-UHFFFAOYSA-N

| density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''Midodrine''', sold under the brand name '''Proamatine''' among others, is an antihypotensive medication used to treat orthostatic hypotension (low blood pressure when standing) and urinary incontinence.<ref name="Proamatine FDA label" /> It is taken by mouth.<ref name="Proamatine FDA label" />

Side effects of midodrine include hypertension (high blood pressure), paresthesia, itching (pruritus), goose bumps, chills, urinary urgency, urinary retention, and urinary frequency.<ref name="Proamatine FDA label" /> Midodrine is a prodrug of its active metabolite desglymidodrine.<ref name="Proamatine FDA label" /> This metabolite acts as a selective agonist of the α1-adrenergic receptor.<ref name="Proamatine FDA label" /> This in turn results in vasoconstriction and increased blood pressure.<ref name="Proamatine FDA label" />

Midodrine was discovered by 1971<ref name="Elks2014" /> and was introduced for medical use in the United States in 1996.<ref>{{cite journal | vauthors = Kymes SM, Sullivan C, Jackson K, Raj SR | title = Real-world droxidopa or midodrine treatment persistence in patients with neurogenic orthostatic hypotension or orthostatic hypotension | journal = Autonomic Neuroscience | volume = 225 | article-number = 102659 | date = May 2020 | pmid = 32200263 | doi = 10.1016/j.autneu.2020.102659 | doi-access = free }}</ref>

==Medical uses== Midodrine is indicated for the treatment of symptomatic orthostatic hypotension. It can reduce dizziness and faints by about a third, but can be limited by troublesome goose bumps, skin itch, gastrointestinal discomfort, chills, elevated blood pressure while lying down, and urinary retention.<ref>{{cite journal | vauthors = Izcovich A, González Malla C, Manzotti M, Catalano HN, Guyatt G | title = Midodrine for orthostatic hypotension and recurrent reflex syncope: A systematic review | journal = Neurology | volume = 83 | issue = 13 | pages = 1170–1177 | date = September 2014 | pmid = 25150287 | doi = 10.1212/WNL.0000000000000815 | s2cid = 5439767 }}</ref> A meta-analysis of clinical trials of midodrine or droxidopa in patients with low blood pressure when standing found that midodrine increased standing blood pressure more than droxidopa but that midodrine but not droxidopa increased the risk of high blood pressure when lying down.<ref>{{cite journal | vauthors = Chen JJ, Han Y, Tang J, Portillo I, Hauser RA, Dashtipour K | title = Standing and Supine Blood Pressure Outcomes Associated With Droxidopa and Midodrine in Patients With Neurogenic Orthostatic Hypotension: A Bayesian Meta-analysis and Mixed Treatment Comparison of Randomized Trials | journal = The Annals of Pharmacotherapy | volume = 52 | issue = 12 | pages = 1182–1194 | date = December 2018 | pmid = 29972032 | doi = 10.1177/1060028018786954 | s2cid = 49674644 }}</ref> Small studies have also shown that midodrine can be used to prevent excessive drops in blood pressure in people requiring dialysis.<ref>{{cite journal | vauthors = Prakash S, Garg AX, Heidenheim AP, House AA | title = Midodrine appears to be safe and effective for dialysis-induced hypotension: a systematic review | journal = Nephrology, Dialysis, Transplantation | volume = 19 | issue = 10 | pages = 2553–2558 | date = October 2004 | pmid = 15280522 | doi = 10.1093/ndt/gfh420 | doi-access = }}</ref>

Midodrine has been used in the complications of cirrhosis. It is also used with octreotide for hepatorenal syndrome; the proposed mechanism is constriction of splanchnic vessels and dilation of renal vasculature. Studies have not been sufficiently well conducted to show a clear place for midodrine.<ref>{{cite journal | vauthors = Karwa R, Woodis CB | title = Midodrine and octreotide in treatment of cirrhosis-related hemodynamic complications | journal = The Annals of Pharmacotherapy | volume = 43 | issue = 4 | pages = 692–699 | date = April 2009 | pmid = 19299324 | doi = 10.1345/aph.1L373 | s2cid = 207263346 }}</ref>

Midodrine is used off-label to increase blood pressure in the treatment of postural orthostatic tachycardia syndrome (POTS) where increased transduction of venous alpha 1 adrenergic receptors increases venous return.<ref name="NarasimhanAggarwalSatish2022">{{cite journal | vauthors = Narasimhan B, Aggarwal D, Satish P, Kantharia B, Aronow WS | title = Postural orthostatic tachycardia syndrome: pathophysiology, management, and experimental therapies | journal = Expert Opin Investig Drugs | volume = 31 | issue = 10 | pages = 1017–1025 | date = October 2022 | pmid = 36094001 | doi = 10.1080/13543784.2022.2121697 | url = }}</ref><ref name="VasavadaVermaSheggari2023">{{cite journal | vauthors = Vasavada AM, Verma D, Sheggari V, Ghetiya S, Chirumamilla PC, Kotak RA, Mahapatra SS, Patel T, Jain M | title = Choices and Challenges With Drug Therapy in Postural Orthostatic Tachycardia Syndrome: A Systematic Review | journal = Cureus | volume = 15 | issue = 5 | article-number = e38887 | date = May 2023 | pmid = 37313107 | pmc = 10259876 | doi = 10.7759/cureus.38887 | doi-access = free | url = }}</ref><ref name="Benarroch2012">{{cite journal | vauthors = Benarroch EE | title = Postural tachycardia syndrome: a heterogeneous and multifactorial disorder | journal = Mayo Clin Proc | volume = 87 | issue = 12 | pages = 1214–1225 | date = December 2012 | pmid = 23122672 | pmc = 3547546 | doi = 10.1016/j.mayocp.2012.08.013 | url = }}</ref>

===Available forms=== Midodrine is available in the form of 2.5, 5, and 10{{nbsp}}mg oral tablets.<ref name="Proamatine FDA label" />

==Contraindications== Midodrine is contraindicated in people with severe organic heart disease, acute kidney disease, urinary retention, pheochromocytoma or thyrotoxicosis.<ref name="Proamatine FDA label" />

==Side effects== Headache, feeling of pressure or fullness in the head, vasodilation or flushing face, scalp tingling, confusion or thinking abnormality, dry mouth, anxiety, and rash, among others.<ref name="Proamatine FDA label" />

==Pharmacology== ===Pharmacodynamics=== Midodrine is a prodrug which forms the active metabolite, desglymidodrine, which is an α1-adrenergic receptor agonist and exerts its actions via activation of α1-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure.<ref name="McClellanWisemanWilde1998" /> Desglymidodrine does not stimulate cardiac β-adrenergic receptors.<ref name="McClellanWisemanWilde1998" />

===Pharmacokinetics=== After oral administration, midodrine is rapidly absorbed. The plasma levels of the prodrug peak after about half an hour, and decline with a half-life of approximately 25{{nbsp}}minutes, while the metabolite reaches peak blood concentrations about 1 to 2 hours after a dose of midodrine and has a half-life of about 3 to{{nbsp}}4 hours. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93%.<ref name="DrugBank">{{cite web | title=Midodrine: Uses, Interactions, Mechanism of Action | website=DrugBank Online | date=31 December 1992 | url=https://go.drugbank.com/drugs/DB00211 | access-date=1 August 2024}}</ref>{{Unreliable medical source|date=August 2025}}

Midodrine and desglymidodrine diffuse poorly across the blood–brain barrier and are therefore peripherally selective and are not associated with effects in the central nervous system.<ref name="Costa-PintoJonesUdy2022">{{cite journal | vauthors = Costa-Pinto R, Jones DA, Udy AA, Warrillow SJ, Bellomo R | title = Midodrine use in critically ill patients: a narrative review | journal = Crit Care Resusc | volume = 24 | issue = 4 | pages = 298–308 | date = December 2022 | pmid = 38047013 | pmc = 10692611 | doi = 10.51893/2022.4.R | url = }}</ref><ref name="Cruz2000">{{cite journal | vauthors = Cruz DN | title = Midodrine: a selective alpha-adrenergic agonist for orthostatic hypotension and dialysis hypotension | journal = Expert Opin Pharmacother | volume = 1 | issue = 4 | pages = 835–840 | date = May 2000 | pmid = 11249519 | doi = 10.1517/14656566.1.4.835 | url = }}</ref><ref name="McClellanWisemanWilde1998">{{cite journal | vauthors = McClellan KJ, Wiseman LR, Wilde MI | title = Midodrine. A review of its therapeutic use in the management of orthostatic hypotension | journal = Drugs Aging | volume = 12 | issue = 1 | pages = 76–86 | date = January 1998 | pmid = 9467688 | doi = 10.2165/00002512-199812010-00007 | url = }}</ref>

Neither midodrine nor desglymidodrine are substrates of monoamine oxidase.<ref name="Proamatine FDA label" />

==Chemistry== Midodrine, also known as 3,6-dimethoxy-β-hydroxy-''N''-aminoethanonyl-2-phenylethylamine, is a substituted phenethylamine derivative.<ref name="Gilden2004" />

Midodrine is an odorless, white, crystalline powder, soluble in water and sparingly soluble in methanol.<ref name="Proamatine FDA label" />

Midodrine's experimental log P is -0.5 and its predicted log P ranges from -0.49 to -0.95.<ref name="PubChem">{{cite web | title=Midodrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/4195 | access-date=1 August 2024}}</ref> The predicted log P of its active metabolite desglymidodrine ranges from -0.01 to 0.15.<ref name="PubChem-Desglymidodrine">{{cite web | title=Desglymidodrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/43260 | access-date=1 August 2024}}</ref>

===Stereochemistry=== Midodrine contains a stereocenter and consists of two enantiomers, making it a racemate; ''i.e.'', a 1:1 mixture of (''R'')- and (''S'')-forms:<ref name="Rote Liste">Rote Liste Service GmbH (Hrsg.): ''Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte)''. Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, {{ISBN|978-3-946057-10-9}}, S. 196.</ref>

{| class="wikitable" style="text-align:center" ! colspan="2"| Enantiomers of midodrine |- | 250px|class=skin-invert-image (''R'')-midodrine CAS number: 133163-25-4 | 250px|class=skin-invert-image (''S'')-midodrine CAS number: 133267-39-7 |}

===Synthesis=== Acylation of 1,4-dimethoxybenzene with chloroacetyl chloride gives the chloroketone 2. The halogen is then converted to the amine 3 by any set of standard schemes, and the ketone reduced to an alcohol with borohydride (4).<ref>{{Cite journal | vauthors = Moreau P, Finiels A, Meric P |date=2000-03-20 |title=Acetylation of dimethoxybenzenes with acetic anhydride in the presence of acidic zeolites |url=https://www.sciencedirect.com/science/article/pii/S1381116999003738 |journal=Journal of Molecular Catalysis A: Chemical |volume=154 |issue=1 |pages=185–192 |doi=10.1016/S1381-1169(99)00373-8 |issn=1381-1169|url-access=subscription }}</ref> Acylation of the amino group in this last intermediate with chloroacetyl chloride affords the amide 5. The halogen is then displaced with azide and the resulting product 6 reduced catalytically to the glycinamide, midodrine (7).<ref>{{cite book | vauthors = Cao T, Martini ML, Park K, Kaniskan HÜ, Jin J | chapter = 8.02 - Pyrimidines and Their Benzo Derivatives |date=2022-01-01 | doi = 10.1016/B978-0-12-818655-8.00041-X | veditors = Black DS, Cossy J, Stevens CV | title = Comprehensive Heterocyclic Chemistry IV |pages=86–228 |place=Oxford |publisher=Elsevier |isbn=978-0-12-818656-5 }}</ref>

thumb|center|700px|class=skin-invert-image|Synthesis of midodrine<ref>{{Cite patent | inventor = Zoelss G |country= DE |number= 2506110 | title = Phenylethanolamine derivs prepn. - by reducing azides, useful as hypertensives | assign1 = Lentia GmbH | gdate = 21 April 1983 | postscript = . }}</ref><ref>K. Wismayr et al., {{Cite patent |country= AT |number= 241435}}; eidem, {{US patent|3340298}} (1965, 1967 both to Chemie Linz Ag).</ref> See also:<ref>Zoelss & W. Karl-Anton Ing {{Cite patent |country= DE |number= 2523735}} (1974 to Lentia GmbH).</ref>

==History== Midodrine was discovered by 1971.<ref name="Elks2014" /> It was approved in the United States by the Food and Drug Administration (FDA) in 1996 for the treatment of dysautonomia and orthostatic hypotension.{{Citation needed|date=August 2024}}

In August 2010, the FDA proposed withdrawing this approval because the manufacturer, Shire plc, failed to complete required studies after the medicine reached the market.<ref>{{cite web |last=Richwine |first=Lisa |title=U.S. proposes withdrawal of Shire hypotension drug|url=https://www.reuters.com/article/business/healthcare-pharmaceuticals/us-proposes-withdrawal-of-shire-hypotension-drug-idUSTRE67F3SE/ |date=August 16, 2010|publisher=Reuters |access-date=21 February 2026 |url-status=live |archive-url=https://web.archive.org/web/20130617030110/http://uk.reuters.com/article/2010/08/16/us-shire-fda-idUKTRE67F3SE20100816 |archive-date=17 June 2013}}</ref><ref>{{cite web| vauthors = O'Riordan M |title=FDA recommends withdrawal of midodrine|url=http://www.theheart.org/article/1110411.do|work=Food and Drug Administration. FDA proposes withdrawal of low blood pressure drug [press release]. August 16, 2010.|publisher=TheHeart.org|access-date=1 April 2011}}</ref> In September 2010, the FDA reversed its decision to remove midodrine from the market and allowed it to remain available while Shire plc collected further data regarding the efficacy and safety of the drug.<ref>[http://healthcare.utah.edu/pharmacy/alerts/497.htm Midodrine (Proamatine, generic) Proposed Market Withdrawal – Update] {{Webarchive|url=https://web.archive.org/web/20120328072841/http://healthcare.utah.edu/pharmacy/alerts/497.htm |date=28 March 2012 }} 10 September 2010.</ref> Shire announced in September 2011, that it was withdrawing completely from supplying midodrine. Midodrine remains available as a generic drug.<ref>{{Cite press release|url=https://www.prnewswire.com/news-releases/shire-provides-update-on-proamatine-midodrine-hcl-130364128.html|title=Shire Provides Update on Proamatine (midodrine HCl)| publisher = Shire plc |via=PR Newswire }}</ref>

==Society and culture== ===Names=== Midodrine is the generic name of the drug and its international nonproprietary name and British Approved Name.<ref name="Elks2014">{{cite book | vauthors = Elks J | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer US | year=2014 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA824 | access-date=30 August 2024 | page=824}}</ref><ref name="MortonHall2012">{{cite book | vauthors = Morton IK, Hall JM | title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms | publisher=Springer Netherlands | year=2012 | isbn=978-94-011-4439-1 | url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA137 | access-date=30 August 2024 | page=137}}</ref><ref name="IndexNominum2004">{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum: International Drug Directory | publisher=Medpharm Scientific Publishers | year=2004 | isbn=978-3-88763-101-7 | url=https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA805 | access-date=30 August 2024 | page=805}}</ref> In the case of the hydrochloride salt, its generic name is midodrine hydrochloride and this is its United States Adopted Name, British Approved Name, and Japanese Accepted Name.<ref name="Elks2014" /><ref name="IndexNominum2004" /> Midodrine is also known by its developmental code names ST-1085 and TS-701.<ref name="Elks2014" /><ref name="IndexNominum2004" /><ref name="Schlesser1990">{{cite book | vauthors = Schlesser JL | title=Drugs Available Abroad: A Guide to Therapeutic Drugs Available and Approved for Use Outside the U. S. | publisher=Gale Research | year=1990 | isbn=978-0-8103-7177-4 | url=https://books.google.com/books?id=2x1tAAAAMAAJ | access-date=30 August 2024 | pages=139,356}}</ref> Midodrine has been sold under brand names including Amatine, Gutron, Midamine, Midon, and Proamatine, among others.<ref name="Elks2014" /><ref name="IndexNominum2004" />

==References== {{Reflist}}

==External links== {{Commons category-inline}}

{{Cardiac stimulants excluding cardiac glycosides}} {{Adrenergic receptor modulators}} {{Phenethylamines}} {{Portal bar | Medicine}} {{Authority control}}

Category:Acetamides Category:Alpha1-adrenergic agonists Category:Antihypotensive agents Category:Cardiac stimulants Category:CYP2D6 inhibitors Category:Methoxyphenethylamines Category:Peripherally selective drugs Category:Phenol ethers Category:Phenylethanolamines Category:Prodrugs Category:Sympathomimetics Category:Vasoconstrictors