Midodrine

Midodrine

Clinical data
Trade names	Proamatine
AHFS/Drugs.com	Monograph
MedlinePlus	a602023
ATC code	C01CA17 (WHO)
Identifiers
IUPAC name (RS)- N-[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]glycinamide
Synonyms	2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxy-ethyl]-acetamide
CAS Number	133163-28-7
PubChem (CID)	4195
IUPHAR/BPS	7240
DrugBank	DB00211
ChemSpider	4050
UNII	6YE7PBM15H
KEGG	D08220
ChEBI	CHEBI:6933
ChEMBL	CHEMBL1076
Chemical and physical data
Formula	C12H18N2O4
Molar mass	254.282 g/mol
3D model (Jmol)	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
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Midodrine (brand names Amatine, ProAmatine, Gutron) is a vasopressor/antihypotensive agent. 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, has failed to complete required studies after the medicine reached the market.^[1][2]

In September 2010, the FDA reversed its decision to remove midodrine from the market and has allowed it to remain available to patients while Shire plc collects further data regarding the efficacy and safety of the drug.^[3] Shire plc announced on September 27, 2011 that it was continuing the process to work with the FDA towards a final approval of the drug.^[4]

Chemical properties

Midodrine is an odorless, white, crystalline powder, soluble in water and sparingly soluble in methanol.

Mechanism of action

Midodrine is a prodrug which forms an active metabolite, desglymidodrine, which is an α₁-receptor agonist and exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure. Desglymidodrine does not stimulate cardiac beta-adrenergic receptors. Desglymidodrine diffuses poorly across the blood–brain barrier, and is therefore not associated with effects on the central nervous system.

Desglymidodrine—a major metabolite

Metabolism

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%.

Indications

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.^[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]

Contraindications

Midodrine is contraindicated in patients with severe organic heart disease, acute renal disease, urinary retention, pheochromocytoma or thyrotoxicosis. Midodrine should not be used in patients with persistent and excessive supine hypertension.

Side effects

Headache; feeling of pressure/fullness in the head, vasodilation/flushing face, confusion/thinking abnormality, dry mouth; nervousness/anxiety and rash.

Synthesis

α-Adrenergic agonist. Prepn:^[8][9] See also:^[10]

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). 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).

See also

• Lisdexamphetamine

References

1. U.S. proposes withdrawal of Shire hypotension drug, Aug 16, 2010.
2. O'Riordan, Michael. "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..
3. Midodrine (ProAmatine, generic) Proposed Market Withdrawal – Update September 10, 2010.
4. Shire Announces Update on ProAmatime September 27, 2011.
5. Izcovich, A.; Gonzalez Malla, C.; Manzotti, M.; Catalano, H. N.; Guyatt, G. (22 August 2014). "Midodrine for orthostatic hypotension and recurrent reflex syncope: A systematic review". Neurology. 83 (13): 1170–1177. doi:10.1212/WNL.0000000000000815. PMID 25150287.
6. Prakash, S; Garg, AX; Heidenheim, AP; House, AA (Oct 2004). "Midodrine appears to be safe and effective for dialysis-induced hypotension: a systematic review.". Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 19 (10): 2553–8. doi:10.1093/ndt/gfh420. PMID 15280522.
7. Karwa, R.; Woodis, C B. (31 March 2009). "Midodrine and Octreotide in Treatment of Cirrhosis-Related Hemodynamic Complications". Annals of Pharmacotherapy. 43 (4): 692–699. doi:10.1345/aph.1L373. PMID 19299324.
8. G. Zoelss, DE 2506110  (1976) via Chem. Abstr., 85:159,718s (1975).
9. K. Wismayr et al., AT 241435 ; eidem, U.S. Patent 3,340,298 (1965, 1967 both to Chemie Linz Ag).
10. Zoelss & W. Karl-Anton Ing DE 2523735  (1974 to Lentia GMBH).

External links

• Midodrine at drugs.com