Chemistry:Midodrine

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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[2] and was introduced for medical use in the United States in 1996.[3]

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.[4] 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.[5] Small studies have also shown that midodrine can be used to prevent excessive drops in blood pressure in people requiring dialysis.[6]

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.[7]

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.[8][9][10]

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]

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.[11] Desglymidodrine does not stimulate cardiac β-adrenergic receptors.[11]

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][11]

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.[15]

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
250 px
(R)-midodrine
CAS number: 133163-25-4 		250 px
(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]

Synthesis of midodrine[21][22] See also:[23]

History

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.[2][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.[2][29] Midodrine is also known by its developmental code names ST-1085 and TS-701.[2][29][30] Midodrine has been sold under brand names including Amatine, Gutron, Midamine, Midon, and Proamatine, among others.[2][29]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 Cite error: Invalid <ref> tag; no text was provided for refs named Proamatine FDA label
  2. ↑ 2.0 2.1 2.2 2.3 2.4 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. 2014. p. 824. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA824. Retrieved 30 August 2024. 
  3. ↑ "Real-world droxidopa or midodrine treatment persistence in patients with neurogenic orthostatic hypotension or orthostatic hypotension". Autonomic Neuroscience 225. May 2020. doi:10.1016/j.autneu.2020.102659. PMID 32200263. 
  4. ↑ "Midodrine for orthostatic hypotension and recurrent reflex syncope: A systematic review". Neurology 83 (13): 1170–1177. September 2014. doi:10.1212/WNL.0000000000000815. PMID 25150287. 
  5. ↑ "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. December 2018. doi:10.1177/1060028018786954. PMID 29972032. 
  6. ↑ "Midodrine appears to be safe and effective for dialysis-induced hypotension: a systematic review". Nephrology, Dialysis, Transplantation 19 (10): 2553–2558. October 2004. doi:10.1093/ndt/gfh420. PMID 15280522. 
  7. ↑ "Midodrine and octreotide in treatment of cirrhosis-related hemodynamic complications". The Annals of Pharmacotherapy 43 (4): 692–699. April 2009. doi:10.1345/aph.1L373. PMID 19299324. 
  8. ↑ "Postural orthostatic tachycardia syndrome: pathophysiology, management, and experimental therapies". Expert Opin Investig Drugs 31 (10): 1017–1025. October 2022. doi:10.1080/13543784.2022.2121697. PMID 36094001. 
  9. ↑ "Choices and Challenges With Drug Therapy in Postural Orthostatic Tachycardia Syndrome: A Systematic Review". Cureus 15 (5). May 2023. doi:10.7759/cureus.38887. PMID 37313107. 
  10. ↑ "Postural tachycardia syndrome: a heterogeneous and multifactorial disorder". Mayo Clin Proc 87 (12): 1214–1225. December 2012. doi:10.1016/j.mayocp.2012.08.013. PMID 23122672. 
  11. ↑ 11.0 11.1 11.2 "Midodrine. A review of its therapeutic use in the management of orthostatic hypotension". Drugs Aging 12 (1): 76–86. January 1998. doi:10.2165/00002512-199812010-00007. PMID 9467688. 
  12. ↑ "Midodrine: Uses, Interactions, Mechanism of Action". 31 December 1992. https://go.drugbank.com/drugs/DB00211. 
  13. ↑ "Midodrine use in critically ill patients: a narrative review". Crit Care Resusc 24 (4): 298–308. December 2022. doi:10.51893/2022.4.R. PMID 38047013. 
  14. ↑ "Midodrine: a selective alpha-adrenergic agonist for orthostatic hypotension and dialysis hypotension". Expert Opin Pharmacother 1 (4): 835–840. May 2000. doi:10.1517/14656566.1.4.835. PMID 11249519. 
  15. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Gilden2004
  16. ↑ "Midodrine". https://pubchem.ncbi.nlm.nih.gov/compound/4195. 
  17. ↑ "Desglymidodrine". https://pubchem.ncbi.nlm.nih.gov/compound/43260. 
  18. ↑ 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.
  19. ↑ "Acetylation of dimethoxybenzenes with acetic anhydride in the presence of acidic zeolites". Journal of Molecular Catalysis A: Chemical 154 (1): 185–192. 2000-03-20. doi:10.1016/S1381-1169(99)00373-8. ISSN 1381-1169. https://www.sciencedirect.com/science/article/pii/S1381116999003738. 
  20. ↑ "8.02 - Pyrimidines and Their Benzo Derivatives". Comprehensive Heterocyclic Chemistry IV. Oxford: Elsevier. 2022-01-01. pp. 86–228. doi:10.1016/B978-0-12-818655-8.00041-X. ISBN 978-0-12-818656-5. 
  21. ↑ Zoelss G, "Phenylethanolamine derivs prepn. - by reducing azides, useful as hypertensives", DE patent 2506110, issued 21 April 1983, assigned to Lentia GmbH.
  22. ↑ K. Wismayr et al., AT patent 241435; eidem, U.S. Patent 3,340,298 (1965, 1967 both to Chemie Linz Ag).
  23. ↑ Zoelss & W. Karl-Anton Ing DE patent 2523735 (1974 to Lentia GmbH).
  24. ↑ U.S. proposes withdrawal of Shire hypotension drug, 16 August 2010.
  25. ↑ "FDA recommends withdrawal of midodrine". Food and Drug Administration. FDA proposes withdrawal of low blood pressure drug [press release]. August 16, 2010.. TheHeart.org. http://www.theheart.org/article/1110411.do. 
  26. ↑ Midodrine (Proamatine, generic) Proposed Market Withdrawal – Update 10 September 2010.
  27. ↑ "Shire Provides Update on Proamatine (midodrine HCl)" (Press release). Shire plc – via PR Newswire.
  28. ↑ Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. 2012. p. 137. ISBN 978-94-011-4439-1. https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA137. Retrieved 30 August 2024. 
  29. ↑ 29.0 29.1 29.2 29.3 Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 805. ISBN 978-3-88763-101-7. https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA805. Retrieved 30 August 2024. 
  30. ↑ Drugs Available Abroad: A Guide to Therapeutic Drugs Available and Approved for Use Outside the U. S.. Gale Research. 1990. pp. 139,356. ISBN 978-0-8103-7177-4. https://books.google.com/books?id=2x1tAAAAMAAJ. Retrieved 30 August 2024. 



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