Midodrine is a
vasopressor/
antihypotensive agent (it raises the blood pressure). Midodrine was approved in the United States by the
Food and Drug Administration (FDA) in 1996 for the treatment of
dysautonomia and
orthostatic hypotension. 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.[2][3] 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.[4] Shire announced on September 22, 2011, that it was withdrawing completely from supplying midodrine and leaving it to several generics to supply the drug.[5]
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.[6] 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.[7] Small studies have also shown that midodrine can be used to prevent excessive drops in blood pressure in people requiring
dialysis.[8]
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.[9]
Contraindications
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.[10]
Side effects
Headache, feeling of pressure/fullness in the head, vasodilation/flushing face, scalp tingling, confusion/thinking abnormality, dry mouth, nervousness/anxiety and rash.[11]
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]
Chemistry
Midodrine is an odorless, white, crystalline powder, soluble in water and sparingly soluble in
methanol.[13]
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:[14]
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).[15] 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).[16]
^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.
^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.
PMID25150287.
S2CID5439767.
^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.
PMID29972032.
S2CID49674644.
^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.
PMID15280522.
^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.
PMID19299324.
S2CID207263346.
^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,
ISBN978-3-946057-10-9, S. 196.
^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.
ISBN978-0-12-818656-5.
^DE 2506110, Zoelss G, "Phenylethanolamine derivs prepn. - by reducing azides, useful as hypertensives", issued 21 April 1983, assigned to Lentia GmbH.