Midodrine

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.{{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 }} 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.{{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 }} Small studies have also shown that midodrine can be used to prevent excessive drops in blood pressure in people requiring dialysis.{{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 = }}

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.{{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 }}

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.{{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 = }}{{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 | pages = e38887 | date = May 2023 | pmid = 37313107 | pmc = 10259876 | doi = 10.7759/cureus.38887 | doi-access = free | url = }}{{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 = }}

Midodrine is available in the form of 2.5, 5, and 10{{nbsp}}mg oral tablets.

Midodrine is contraindicated in patients with severe organic heart disease, acute kidney disease, urinary retention, pheochromocytoma or thyrotoxicosis. Midodrine should not be used in patients with persistent and excessive supine hypertension.{{Cite web |title=Midodrine - FDA prescribing information, side effects and uses |url=https://www.drugs.com/pro/midodrine.html |access-date=2022-06-30 |website=Drugs.com |language=en}}

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.{{Cite web|url=https://www.mayoclinic.org/drugs-supplements/midodrine-oral-route/side-effects/drg-20064821|title=Midodrine (Oral Route) Side Effects - Mayo Clinic|website=www.mayoclinic.org}}

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. Desglymidodrine does not stimulate cardiac β-adrenergic receptors.{{Citation needed|date=February 2025}}

File:Desglymidodrine.svg.]]{{clear left}}

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%.

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.{{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 = }}{{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 = }}{{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 = }}

Neither midodrine nor desglymidodrine are substrates of monoamine oxidase.

Midodrine, also known as 3,6-dimethoxy-β-hydroxy-N-aminoethanonyl-2-phenylethylamine, is a substituted phenethylamine derivative.

Midodrine is an odorless, white, crystalline powder, soluble in water and sparingly soluble in methanol.{{Cite web |title=DailyMed - MIDODRINE HCL- midodrine hydrochloride tablet |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24847065-0be0-46eb-a084-7e5425a8be73 |access-date=2023-01-05 |website=DailyMed}}

Midodrine's experimental log P is -0.5 and its predicted log P ranges from -0.49 to -0.95.{{cite web | title=Midodrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/4195 | access-date=1 August 2024}}{{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}} The predicted log P of its active metabolite desglymidodrine ranges from -0.01 to 0.15.{{cite web | title=Desglymidodrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/43260 | access-date=1 August 2024}}{{cite web | title=Metabolite desglymidodrine | website=DrugBank Online | url=https://go.drugbank.com/metabolites/DBMET00829 | access-date=1 August 2024}}

Midodrine contains a stereocenter and consists of two enantiomers, making it a racemate; i.e., a 1:1 mixture of (R)- and (S)-forms: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.

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).{{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 |language=en |volume=154 |issue=1 |pages=185–192 |doi=10.1016/S1381-1169(99)00373-8 |issn=1381-1169|url-access=subscription }} 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).{{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 |language=en |isbn=978-0-12-818656-5 }}

File:Midodrine synthesis.svg

Midodrine was discovered by 1971. 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.[https://archive.today/20120720172637/http://uk.reuters.com/article/idUKTRE67F3SE20100816 U.S. proposes withdrawal of Shire hypotension drug], 16 August 2010.{{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}} In September 2010, the FDA reversed its decision to remove midodrine from the market and allowed it to remain available to patients while Shire plc collected further data regarding the efficacy and safety of the drug.[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. Shire announced on September 22, 2011, that it was withdrawing completely from supplying midodrine. Midodrine remains available as a generic drug.{{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)| author = Shire plc |website=www.prnewswire.com}}

Midodrine is the generic name of the drug and its {{Abbrlink|INN|International Nonproprietary Name}}, {{Abbrlink|BAN|British Approved Name}}, and {{Abbrlink|DCF|Dénomination Commune Française}}, while its {{Abbrlink|DCIT|Denominazione Comune Italiana}} is midodrina.{{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}}{{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}}{{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}} In the case of the hydrochloride salt, its generic name is midodrine hydrochloride and this is its {{Abbrlink|USAN|United States Adopted Name}}, {{Abbrlink|BANM|British Approved Name}}, and {{Abbrlink|JAN|Japanese Accepted Name}}. The drug is also known by its developmental code names ST-1085 and TS-701.{{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}} Midodrine has been sold under brand names including Amatine, Gutron, Midamine, Midon, and ProAmatine, among others.

Midodrine was under development for the treatment of chronic fatigue syndrome, but no recent development for this indication has been reported.

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