Midodrine

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Midodrine
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Systematic (IUPAC) name
(RS)- N-[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]glycinamide
Clinical data
Trade names Proamatine
AHFS/Drugs.com monograph
MedlinePlus a602023
Identifiers
CAS Number 133163-28-7 YesY
ATC code C01CA17 (WHO)
PubChem CID: 4195
IUPHAR/BPS 7240
DrugBank DB00211 YesY
ChemSpider 4050 YesY
UNII 6YE7PBM15H YesY
KEGG D08220 YesY
ChEBI CHEBI:6933 YesY
ChEMBL CHEMBL1076 N
Synonyms 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxy-ethyl]-acetamide
Chemical data
Formula C12H18N2O4
Molecular mass 254.282 g/mol
  • O=C(NCC(O)c1cc(OC)ccc1OC)CN
  • 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) YesY
  • Key:PTKSEFOSCHHMPD-UHFFFAOYSA-N YesY
 NYesY (what is this?)  (verify)

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.

File:Desglymidodrine.svg
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.[citation needed]

Synthesis

File:Midodrine synthesis.svg
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

References

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External links

  1. ↑ U.S. proposes withdrawal of Shire hypotension drug, Aug 16, 2010.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found..
  3. ↑ Midodrine (ProAmatine, generic) Proposed Market Withdrawal – Update September 10, 2010.
  4. ↑ Shire Announces Update on ProAmatime September 27, 2011.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  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).
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