Midodrine

Midodrine
	Above: molecular structure of midodrine Below: 3D representation of a midodrine molecule
Clinical data
Trade names	Proamatine, others
Other names	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
AHFS/Drugs.com	Monograph
MedlinePlus	a616030
License data	US DailyMed: Midodrine;
Pregnancy; category	AU: C; ;
Routes of; administration	By mouth
Drug class	α1-Adrenergic receptor agonist; Antihypotensive agent
ATC code	C01CA17 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); US: ℞-only;
Pharmacokinetic data
Bioavailability	93% (as desglymidodrine)
Metabolism	Deglycination
Metabolites	• Desglymidodrine
Onset of action	≤1 hour
Elimination half-life	Midodrine: 0.5 hours; Desglymidodrine: 2–4 hours
Duration of action	2–6 hours
Identifiers
	IUPAC name (RS)-N-[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]glycinamide;
CAS Number	42794-76-3 ;
PubChem CID	4195;
IUPHAR/BPS	7240;
DrugBank	DB00211;
ChemSpider	4050;
UNII	6YE7PBM15H;
KEGG	D08220;
ChEBI	CHEBI:6933;
ChEMBL	ChEMBL1201212;
CompTox Dashboard (EPA)	DTXSID0023321 ;
ECHA InfoCard	100.151.349 100.050.842, 100.151.349
Chemical and physical data
Formula	C12H18N2O4
Molar mass	254.286 g·mol−1
3D model (JSmol)	Interactive image;
Chirality	Racemic mixture
	SMILES O=C(NCC(O)c1cc(OC)ccc1OC)CN;
	InChI InChI=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) ; Key:PTKSEFOSCHHMPD-UHFFFAOYSA-N ;

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.^[1] It is taken by mouth.^[1]

Side effects of midodrine include hypertension (high blood pressure), paresthesia, itching (pruritus), goose bumps, chills, urinary urgency, urinary retention, and urinary frequency.^[1] Midodrine is a prodrug of its active metabolite desglymidodrine.^[1] This metabolite acts as a selective agonist of the α₁-adrenergic receptor.^[1] This in turn results in vasoconstriction and increased blood pressure.^[1]

Midodrine was discovered by 1971^[3] and was introduced for medical use in the United States in 1996.^[4]

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.^[5] 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.^[6] Small studies have also shown that midodrine can be used to prevent excessive drops in blood pressure in people requiring dialysis.^[7]

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.^[8]

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.^[9]^[10]^[11]

Available forms

Midodrine is available in the form of 2.5, 5, and 10 mg oral tablets.^[1]

Contraindications

Midodrine is contraindicated in people with severe organic heart disease, acute kidney disease, urinary retention, pheochromocytoma or thyrotoxicosis.^[1]

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.^[1]

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 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 4 hours. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93%.^[12]^{[unreliable medical source?]}

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.^[13]^[14]^[15]

Neither midodrine nor desglymidodrine are substrates of monoamine oxidase.^[1]

Chemistry

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

Midodrine is an odorless, white, crystalline powder, soluble in water and sparingly soluble in methanol.^[1]

Midodrine's experimental log P is -0.5 and its predicted log P ranges from -0.49 to -0.95.^[16] The predicted log P of its active metabolite desglymidodrine ranges from -0.01 to 0.15.^[17]

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:^[18]

Enantiomers of midodrine
(R)-midodrine CAS number: 133163-25-4	(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).^[19] 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).^[20]

History

Midodrine was discovered by 1971.^[3] 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]}

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.^[24]^[25] 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.^[26] Shire announced in September 2011, that it was withdrawing completely from supplying midodrine. Midodrine remains available as a generic drug.^[27]

Society and culture

Names

Midodrine is the generic name of the drug and its international nonproprietary name and British Approved Name.^[3]^[28]^[29] 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.^[3]^[29] Midodrine is also known by its developmental code names ST-1085 and TS-701.^[3]^[29]^[30] Midodrine has been sold under brand names including Amatine, Gutron, Midamine, Midon, and Proamatine, among others.^[3]^[29]

References

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q "Proamatine- midodrine hydrochloride tablet". DailyMed. Retrieved 14 August 2021.
^ ^a ^b ^c ^d ^e ^f ^g Gilden JL (2004). "Midodrine and Other Sympathomimetics". Primer on the Autonomic Nervous System. Elsevier. pp. 413–415. doi:10.1016/b978-012589762-4/50113-4. ISBN 978-0-12-589762-4.
^ ^a ^b ^c ^d ^e ^f Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 824. ISBN 978-1-4757-2085-3. Retrieved 30 August 2024.
^ Kymes SM, Sullivan C, Jackson K, Raj SR (May 2020). "Real-world droxidopa or midodrine treatment persistence in patients with neurogenic orthostatic hypotension or orthostatic hypotension". Autonomic Neuroscience. 225 102659. doi:10.1016/j.autneu.2020.102659. PMID 32200263.
^ Izcovich A, González Malla C, Manzotti M, Catalano HN, Guyatt G (September 2014). "Midodrine for orthostatic hypotension and recurrent reflex syncope: A systematic review". Neurology. 83 (13): 1170–1177. doi:10.1212/WNL.0000000000000815. PMID 25150287. S2CID 5439767.
^ Chen JJ, Han Y, Tang J, Portillo I, Hauser RA, Dashtipour K (December 2018). "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". The Annals of Pharmacotherapy. 52 (12): 1182–1194. doi:10.1177/1060028018786954. PMID 29972032. S2CID 49674644.
^ Prakash S, Garg AX, Heidenheim AP, House AA (October 2004). "Midodrine appears to be safe and effective for dialysis-induced hypotension: a systematic review". Nephrology, Dialysis, Transplantation. 19 (10): 2553–2558. doi:10.1093/ndt/gfh420. PMID 15280522.
^ Karwa R, Woodis CB (April 2009). "Midodrine and octreotide in treatment of cirrhosis-related hemodynamic complications". The Annals of Pharmacotherapy. 43 (4): 692–699. doi:10.1345/aph.1L373. PMID 19299324. S2CID 207263346.
^ Narasimhan B, Aggarwal D, Satish P, Kantharia B, Aronow WS (October 2022). "Postural orthostatic tachycardia syndrome: pathophysiology, management, and experimental therapies". Expert Opin Investig Drugs. 31 (10): 1017–1025. doi:10.1080/13543784.2022.2121697. PMID 36094001.
^ Vasavada AM, Verma D, Sheggari V, Ghetiya S, Chirumamilla PC, Kotak RA, et al. (May 2023). "Choices and Challenges With Drug Therapy in Postural Orthostatic Tachycardia Syndrome: A Systematic Review". Cureus. 15 (5): e38887. doi:10.7759/cureus.38887. PMC 10259876. PMID 37313107.{{cite journal}}: CS1 maint: article number as page number (link)
^ Benarroch EE (December 2012). "Postural tachycardia syndrome: a heterogeneous and multifactorial disorder". Mayo Clin Proc. 87 (12): 1214–1225. doi:10.1016/j.mayocp.2012.08.013. PMC 3547546. PMID 23122672.
^ "Midodrine: Uses, Interactions, Mechanism of Action". DrugBank Online. 31 December 1992. Retrieved 1 August 2024.
^ Costa-Pinto R, Jones DA, Udy AA, Warrillow SJ, Bellomo R (December 2022). "Midodrine use in critically ill patients: a narrative review". Crit Care Resusc. 24 (4): 298–308. doi:10.51893/2022.4.R. PMC 10692611. PMID 38047013.
^ Cruz DN (May 2000). "Midodrine: a selective alpha-adrenergic agonist for orthostatic hypotension and dialysis hypotension". Expert Opin Pharmacother. 1 (4): 835–840. doi:10.1517/14656566.1.4.835. PMID 11249519.
^ McClellan KJ, Wiseman LR, Wilde MI (January 1998). "Midodrine. A review of its therapeutic use in the management of orthostatic hypotension". Drugs Aging. 12 (1): 76–86. doi:10.2165/00002512-199812010-00007. PMID 9467688.
^ "Midodrine". PubChem. Retrieved 1 August 2024.
^ "Desglymidodrine". PubChem. Retrieved 1 August 2024.
^ 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.
^ Moreau P, Finiels A, Meric P (20 March 2000). "Acetylation of dimethoxybenzenes with acetic anhydride in the presence of acidic zeolites". Journal of Molecular Catalysis A: Chemical. 154 (1): 185–192. doi:10.1016/S1381-1169(99)00373-8. ISSN 1381-1169.
^ Cao T, Martini ML, Park K, Kaniskan HÜ, Jin J (1 January 2022). "8.02 - Pyrimidines and Their Benzo Derivatives". In Black DS, Cossy J, Stevens CV (eds.). Comprehensive Heterocyclic Chemistry IV. Oxford: Elsevier. pp. 86–228. doi:10.1016/B978-0-12-818655-8.00041-X. ISBN 978-0-12-818656-5.
^ DE 2506110, Zoelss G, "Phenylethanolamine derivs prepn. - by reducing azides, useful as hypertensives", issued 21 April 1983, assigned to Lentia GmbH.
^ K. Wismayr et al., AT 241435 ; eidem, U.S. patent 3,340,298 (1965, 1967 both to Chemie Linz Ag).
^ Zoelss & W. Karl-Anton Ing DE 2523735 (1974 to Lentia GmbH).
^ U.S. proposes withdrawal of Shire hypotension drug, 16 August 2010.
^ O'Riordan M. "FDA recommends withdrawal of midodrine". Food and Drug Administration. FDA proposes withdrawal of low blood pressure drug [press release]. August 16, 2010. TheHeart.org. Retrieved 1 April 2011.
^ Midodrine (Proamatine, generic) Proposed Market Withdrawal – Update Archived 28 March 2012 at the Wayback Machine 10 September 2010.
^ "Shire Provides Update on Proamatine (midodrine HCl)" (Press release). Shire plc – via PR Newswire.
^ Morton IK, Hall JM (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. p. 137. ISBN 978-94-011-4439-1. Retrieved 30 August 2024.
^ ^a ^b ^c ^d Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 805. ISBN 978-3-88763-101-7. Retrieved 30 August 2024.
^ Schlesser JL (1990). Drugs Available Abroad: A Guide to Therapeutic Drugs Available and Approved for Use Outside the U. S. Gale Research. pp. 139, 356. ISBN 978-0-8103-7177-4. Retrieved 30 August 2024.