Midodrine

Identification

Summary

Midodrine is an alpha-adrenergic agonist used to treat orthostatic hypotension.

Brand Names
Proamatine
Generic Name
Midodrine
DrugBank Accession Number
DB00211
Background

An ethanolamine derivative that is an adrenergic alpha agonist. It is used as a vasoconstrictor agent in the treatment of hypotension.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 254.2823
Monoisotopic: 254.126657074
Chemical Formula
C12H18N2O4
Synonyms
  • (±)-2-amino-N-(β-hydroxy-2,5-dimethoxyphenethyl)acetamide
  • 1-(2',5'-Dimethoxyphenyl)-2-glycinamidoethanol
  • 2-Amino-N-(2,5-dimethoxy-beta-hydroxyphenethyl)acetamide
  • DL-N1-(beta-Hydroxy-2,5-dimethoxyphenethyl)glycinamid
  • Midodrin
  • Midodrina
  • Midodrine
  • Midodrinum
External IDs
  • ST 1085
  • ST-1085

Pharmacology

Indication

For the treatment of symptomatic orthostatic hypotension (OH).

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofSymptomatic orthostatic hypotension••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Midodrine is a prodrug, i.e., the therapeutic effect of orally administered midodrine is due to the major metabolite desglymidodrine formed by deglycination of midodrine. Administration of midodrine results in a rise in standing, sitting, and supine systolic and diastolic blood pressure in patients with orthostatic hypotension of various etiologies. Standing systolic blood pressure is elevated by approximately 15 to 30 mmHg at 1 hour after a 10-mg dose of midodrine, with some effect persisting for 2 to 3 hours. Midodrine has no clinically significant effect on standing or supine pulse rates in patients with autonomic failure.

Mechanism of action

Midodrine undergoes metabolism to form its pharmacologically active metabolite, desglymidodrine. Desglymidodrine acts as an agonist at the alpha1-adrenergic receptors expressed in the arteriolar and venous vasculature. Activation of alpha1-adrenergic receptor signaling pathways lead to an increase in the vascular tone and elevation of blood pressure. Desglymidodrine is reported to have negligible effect on the cardiac beta-adrenergic receptors.

TargetActionsOrganism
AAlpha-1A adrenergic receptor
agonist
Humans
AAlpha-1B adrenergic receptor
agonist
Humans
UAlpha-1D adrenergic receptor
agonist
Humans
Absorption

Rapidly absorbed following oral administration. The peak plasma concentrations of the prodrug, desglymidodrine, is reached about half an hour following drug administration. The metabolites reach their peak plasma concentrations at about 1 to 2 hours following drug administration. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93% and is not affected by food. As desglymidodrine displays poor diffusibility across the blood-brain barrier, it is expected to have minimal effects on the central nervous system.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Thorough metabolic studies have not been conducted, but it appears that deglycination of midodrine to desglymidodrine takes place in many tissues, and both compounds are metabolized in part by the liver.

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Route of elimination

Not Available

Half-life

The metabolites display a half-life of about 3 to 4 hours.

Clearance
  • Renal cl=385 mL/minute
Adverse Effects
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Toxicity

Symptoms of overdose could include hypertension, piloerection (goosebumps), a sensation of coldness and urinary retention. The single doses that would be associated with symptoms of overdosage or would be potentially life- threatening are unknown. The oral LD50 is approximately 30 to 50 mg/kg in rats, 675 mg/kg in mice, and 125 to 160 mg/kg in dogs. Desglymidodrine is dialyzable.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcebutololThe therapeutic efficacy of Midodrine can be decreased when used in combination with Acebutolol.
AceclofenacThe risk or severity of hypertension can be increased when Midodrine is combined with Aceclofenac.
AcemetacinThe risk or severity of hypertension can be increased when Midodrine is combined with Acemetacin.
AcetyldigitoxinAcetyldigitoxin may increase the bradycardic, atrioventricular blocking (AV block), and arrhythmogenic activities of Midodrine.
Acetylsalicylic acidThe risk or severity of hypertension can be increased when Midodrine is combined with Acetylsalicylic acid.
Food Interactions
  • Take with or without food. The absorption is unaffected by food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Midodrine hydrochloride59JV96YTXV43218-56-0MGCQZNBCJBRZDT-UHFFFAOYSA-N
Product Images
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AmatineTablet2.5 mgOralShire Pharma Canada Ulc1992-12-312010-09-30Canada flag
AmatineTablet5 mgOralShire Pharma Canada Ulc1992-12-312010-10-04Canada flag
MidodrineTablet5 mgOralSanis Health Inc2023-05-31Not applicableCanada flag
MidodrineTablet2.5 mgOralSanis Health Inc2023-05-31Not applicableCanada flag
ProAmatineTablet2.5 mg/1OralShire1996-09-062010-12-31US flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Apo-midodrineTablet2.5 mgOralApotex Corporation2006-06-13Not applicableCanada flag
Apo-midodrineTablet5 mgOralApotex Corporation2006-06-13Not applicableCanada flag
Jamp MidodrineTablet5 mgOralJamp Pharma Corporation2022-02-21Not applicableCanada flag
Jamp MidodrineTablet2.5 mgOralJamp Pharma Corporation2022-02-21Not applicableCanada flag
Mar-midodrineTablet5 mgOralMarcan Pharmaceuticals Inc2018-08-03Not applicableCanada flag

Categories

ATC Codes
C01CA17 — Midodrine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as dimethoxybenzenes. These are organic aromatic compounds containing a monocyclic benzene moiety carrying exactly two methoxy groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Methoxybenzenes
Direct Parent
Dimethoxybenzenes
Alternative Parents
Phenoxy compounds / Anisoles / Alkyl aryl ethers / Secondary alcohols / Propargyl-type 1,3-dipolar organic compounds / Carboximidic acids / Organopnictogen compounds / Monoalkylamines / Hydrocarbon derivatives / Aromatic alcohols
Substituents
Alcohol / Alkyl aryl ether / Amine / Anisole / Aromatic alcohol / Aromatic homomonocyclic compound / Carboximidic acid / Carboximidic acid derivative / Dimethoxybenzene / Ether
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
aromatic ether, amino acid amide, secondary alcohol (CHEBI:6933)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
6YE7PBM15H
CAS number
42794-76-3
InChI Key
PTKSEFOSCHHMPD-UHFFFAOYSA-N
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)
IUPAC Name
2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide
SMILES
COC1=CC(C(O)CNC(=O)CN)=C(OC)C=C1

References

Synthesis Reference

Anup K. Ray, Hiren Patel, Mahendra R. Patel, "Synthesis of midodrine HCI from a novel intermediate 1-(2',5'-dimethoxyphenyl)-2-azidoethanone." U.S. Patent US6201153, issued July, 1965.

US6201153
General References
  1. Hebenstreit G: [Treatment of hypotension caused by psychopharmacological drugs (author's transl)]. Wien Med Wochenschr. 1981 Feb 28;131(4):109-12. [Article]
  2. Tsuda M, Terada T, Irie M, Katsura T, Niida A, Tomita K, Fujii N, Inui K: Transport characteristics of a novel peptide transporter 1 substrate, antihypotensive drug midodrine, and its amino acid derivatives. J Pharmacol Exp Ther. 2006 Jul;318(1):455-60. Epub 2006 Apr 5. [Article]
Human Metabolome Database
HMDB0014356
KEGG Drug
D08220
KEGG Compound
C07890
PubChem Compound
4195
PubChem Substance
46507373
ChemSpider
4050
RxNav
6963
ChEBI
6933
ChEMBL
CHEMBL1201212
Therapeutic Targets Database
DAP000229
PharmGKB
PA164749381
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Midodrine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingSupportive CareHypothermia, Accidental / Mild Cognitive Impairment (MCI) / Quadriplegia1
4Active Not RecruitingTreatmentVasovagal Syncope1
4CompletedNot AvailableHypothermia, Accidental / Mild Cognitive Impairment (MCI) / Quadriplegia1
4CompletedHealth Services ResearchSeptic Shock1
4CompletedPreventionGastrointestinal Hemorrhage / Hepatic Encephalopathy (HE) / Hyponatremia / Kidney Failure / Sepsis1

Pharmacoeconomics

Manufacturers
  • Apotex inc etobicoke site
  • Impax pharmaceuticals
  • Mylan pharmaceuticals inc
  • Sandoz inc
  • Upsher smith laboratories inc
  • Shire development inc
Packagers
  • Actavis Group
  • Amerisource Health Services Corp.
  • Apotex Inc.
  • Eon Labs
  • Global Pharmaceuticals
  • Heartland Repack Services LLC
  • Impax Laboratories Inc.
  • Kaiser Foundation Hospital
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Nycomed Inc.
  • Physicians Total Care Inc.
  • Rebel Distributors Corp.
  • Resource Optimization and Innovation LLC
  • Shire Inc.
  • UDL Laboratories
  • Upsher Smith Laboratories
  • Vangard Labs Inc.
Dosage Forms
FormRouteStrength
TabletOral5 mg
Injection, solution
Solution / dropsOral
TabletOral
Solution / dropsOral1 %
Solution / drops; suspension / dropsOral10 mg
Tablet, coatedOral5 mg
Tablet, coatedOral500000 mg
TabletOral10 mg/1
TabletOral2.5 mg/1
TabletOral2.5 mg
TabletOral5 mg/1
Prices
Unit descriptionCostUnit
Proamatine 10 mg tablet5.91USD tablet
Midodrine hcl 10 mg tablet4.93USD tablet
Proamatine 5 mg tablet3.08USD tablet
Midodrine hcl 5 mg tablet2.47USD tablet
Proamatine 2.5 mg tablet1.53USD tablet
Midodrine hcl 2.5 mg tablet1.23USD tablet
Apo-Midodrine 5 mg Tablet0.59USD tablet
Apo-Midodrine 2.5 mg Tablet0.35USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)200 to 203°CNot Available
water solubilitySolubleNot Available
logP-0.5Not Available
pKa7.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility4.45 mg/mLALOGPS
logP-0.49ALOGPS
logP-0.95Chemaxon
logS-1.8ALOGPS
pKa (Strongest Acidic)13.77Chemaxon
pKa (Strongest Basic)8.14Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area93.81 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity66.22 m3·mol-1Chemaxon
Polarizability26.65 Å3Chemaxon
Number of Rings1Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.7686
Blood Brain Barrier-0.856
Caco-2 permeable-0.7382
P-glycoprotein substrateSubstrate0.784
P-glycoprotein inhibitor INon-inhibitor0.9781
P-glycoprotein inhibitor IINon-inhibitor0.9866
Renal organic cation transporterNon-inhibitor0.8896
CYP450 2C9 substrateNon-substrate0.8519
CYP450 2D6 substrateNon-substrate0.7593
CYP450 3A4 substrateNon-substrate0.5595
CYP450 1A2 substrateInhibitor0.8848
CYP450 2C9 inhibitorNon-inhibitor0.9385
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorInhibitor0.8993
CYP450 3A4 inhibitorNon-inhibitor0.867
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9316
Ames testNon AMES toxic0.774
CarcinogenicityNon-carcinogens0.8613
BiodegradationNot ready biodegradable0.9595
Rat acute toxicity2.3137 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9772
hERG inhibition (predictor II)Non-inhibitor0.8604
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0019-9420000000-7d9c097f5836b8a5fae7
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-000t-0910000000-e550d105839acbb60ad3
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0007-3900000000-64b9fd3e180615fc1cd9
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-002b-2900000000-c7a005bb253ca6ffdeb7
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-01q0-0900000000-8cdccfe291eb7aa775b4
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0mb9-6900000000-f21d9dd6bd17659bece2
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-00kf-4910000000-e52d27b07ec619d21e3d
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-163.5543844
predicted
DarkChem Lite v0.1.0
[M-H]-157.73965
predicted
DeepCCS 1.0 (2019)
[M+H]+163.4477844
predicted
DarkChem Lite v0.1.0
[M+H]+160.09764
predicted
DeepCCS 1.0 (2019)
[M+Na]+163.3959844
predicted
DarkChem Lite v0.1.0
[M+Na]+166.1908
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Gene Name
ADRA1A
Uniprot ID
P35348
Uniprot Name
Alpha-1A adrenergic receptor
Molecular Weight
51486.005 Da
References
  1. Buckner SA, Milicic I, Daza AV, Meyer MD, Altenbach RJ, Williams M, Sullivan JP, Brioni JD: ABT-866, a novel alpha(1A)-adrenoceptor agonist with antagonist properties at the alpha(1B)- and alpha(1D)-adrenoceptor subtypes. Eur J Pharmacol. 2002 Aug 2;449(1-2):159-65. [Article]
  2. Taniguchi N, Hamada K, Ogasawara T, Ukai Y, Yoshikuni Y, Kimura K: NS-49, an alpha 1A-adrenoceptor agonist, selectively increases intraurethral pressure in dogs. Eur J Pharmacol. 1996 Dec 27;318(1):117-22. [Article]
  3. Altenbach RJ, Khilevich A, Kolasa T, Rohde JJ, Bhatia PA, Patel MV, Searle XB, Yang F, Bunnelle WH, Tietje K, Bayburt EK, Carroll WA, Meyer MD, Henry R, Buckner SA, Kuk J, Daza AV, Milicic IV, Cain JC, Kang CH, Ireland LM, Carr TL, Miller TR, Hancock AA, Nakane M, Esbenshade TA, Brune ME, O'Neill AB, Gauvin DM, Katwala SP, Holladay MW, Brioni JD, Sullivan JP: Synthesis and structure-activity studies on N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide, an imidazole-containing alpha(1A)-adrenoceptor agonist. J Med Chem. 2004 Jun 3;47(12):3220-35. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Gene Name
ADRA1B
Uniprot ID
P35368
Uniprot Name
Alpha-1B adrenergic receptor
Molecular Weight
56835.375 Da
References
  1. Altenbach RJ, Khilevich A, Kolasa T, Rohde JJ, Bhatia PA, Patel MV, Searle XB, Yang F, Bunnelle WH, Tietje K, Bayburt EK, Carroll WA, Meyer MD, Henry R, Buckner SA, Kuk J, Daza AV, Milicic IV, Cain JC, Kang CH, Ireland LM, Carr TL, Miller TR, Hancock AA, Nakane M, Esbenshade TA, Brune ME, O'Neill AB, Gauvin DM, Katwala SP, Holladay MW, Brioni JD, Sullivan JP: Synthesis and structure-activity studies on N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide, an imidazole-containing alpha(1A)-adrenoceptor agonist. J Med Chem. 2004 Jun 3;47(12):3220-35. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Alpha1-adrenergic receptor activity
Specific Function
This alpha-adrenergic receptor mediates its effect through the influx of extracellular calcium.
Gene Name
ADRA1D
Uniprot ID
P25100
Uniprot Name
Alpha-1D adrenergic receptor
Molecular Weight
60462.205 Da
References
  1. Altenbach RJ, Khilevich A, Meyer MD, Buckner SA, Milicic I, Daza AV, Brune ME, O'Neill AB, Gauvin DM, Cain JC, Nakane M, Holladay MW, Williams M, Brioni JD, Sullivan JP: N-[3-(1H-imidazol-4-ylmethyl)phenyl]ethanesulfonamide (ABT-866, 1),(1) a novel alpha(1)-adrenoceptor ligand with an enhanced in vitro and in vivo profile relative to phenylpropanolamine and midodrine. J Med Chem. 2002 Sep 26;45(20):4395-7. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Platts SH, Shi SJ, Meck JV: Akathisia with combined use of midodrine and promethazine. JAMA. 2006 May 3;295(17):2000-1. [Article]
  2. Flockhart Table of Drug Interactions [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Proton-dependent oligopeptide secondary active transmembrane transporter activity
Specific Function
Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. May constitute a major route for the absorption of protein digestion end-products.
Gene Name
SLC15A1
Uniprot ID
P46059
Uniprot Name
Solute carrier family 15 member 1
Molecular Weight
78805.265 Da
References
  1. Tsuda M, Terada T, Irie M, Katsura T, Niida A, Tomita K, Fujii N, Inui K: Transport characteristics of a novel peptide transporter 1 substrate, antihypotensive drug midodrine, and its amino acid derivatives. J Pharmacol Exp Ther. 2006 Jul;318(1):455-60. Epub 2006 Apr 5. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 18, 2024 16:48