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Identification
Name Hydralazine
Accession Number DB01275
Type small molecule
Groups approved
Description

A direct-acting vasodilator that is used as an antihypertensive agent. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Hydralazine hydrochloride
Brand names
  • Apresoline
Brand name mixtures
  • BiDil (isosorbide dinitrate + hydralazine hydrochloride)
Categories
  • Antihypertensive Agents
  • Vasodilator Agents
CAS number 86-54-4
Weight Average: 160.1759
Monoisotopic: 160.074896276
Chemical Formula C8H8N4
InChI Key InChIKey=RPTUSVTUFVMDQK-UHFFFAOYSA-N
InChI
InChI=1S/C8H8N4/c9-11-8-7-4-2-1-3-6(7)5-10-12-8/h1-5H,9H2,(H,11,12)
Plain Text
IUPAC Name
1-hydrazinylphthalazine
SMILES
NNC1=C2C=CC=CC2=CN=N1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phthalazines
Substructures
  • Benzene and Derivatives
  • Phthalazines
  • Pyridazines
  • Heterocyclic compounds
  • Aromatic compounds
  • Hydrazine Derivatives
Pharmacology
Indication For the treatment of essential hypertension, alone or as an adjunct. Also for the management of severe hypertension when the drug cannot be given orally or when blood pressure must be lowered immediately, congestive heart failure (in combination with cardiac glycosides and diuretics and/or with isosorbide dinitrate), and hypertension secondary to pre-eclampsia/eclampsia.
Pharmacodynamics A vasodilator, hydralazine works by relaxing blood vessels (arterioles more than venules) and increasing the supply of blood and oxygen to the heart while reducing its workload. It also functions as an antioxidant. It inhibits membrane-bound enzymes that form reactive oxygen species, such as superoxides. Excessive superoxide counteracts NO-induced vasodilation. It is commonly used in the condition of pregnancy called preeclampsia.
Mechanism of action Although the precise mechanism of action of hydralazine is not fully understood, the major effects are on the cardiovascular system. Hydralazine apparently lowers blood pressure by exerting a peripheral vasodilating effect through a direct relaxation of vascular smooth muscle. It has also been suggested that cyclic 3',5'-adenosine monophosphate (cyclic AMP) mediates, at least partly, the relaxation of arterial smooth muscle by altering cellular calcium metabolism, which interferes with the calcium movements within the vascular smooth muscle that are responsible for initiating or maintaining the contractile state. In hypertensive patients, the hydralazine-induced decrease in blood pressure is accompanied by increased heart rate, cardiac output, and stroke volume, probably because of a reflex response to decreased peripheral resistance. The drug has no direct effect on the heart. Hydralazine may increase pulmonary arterial pressure, as well as coronary, splanchnic, cerebral, and renal blood flow. The preferential dilatation of arterioles, as compared to veins, minimizes postural hypotension and promotes the increase in cardiac output. Hydralazine usually increases renin activity in plasma, presumably as a result of increased secretion of renin by the renal juxtaglomerular cells in response to reflex sympathetic discharge. This increase in renin activity leads to the production of angiotensin II, which then causes stimulation of aldosterone and consequent sodium reabsorption. Tolerance to the antihypertensive effect of the drug develops during prolonged therapy, especially if a diuretic is not administered concurrently. In patients with CHF, hydralazine decreases systemic vascular resistance and increases cardiac output.
Absorption Hydralazine is rapidly and extensively absorbed (up to 90%) from the gastrointestinal tract and undergoes extensive first-pass metabolism by genetic polymorphic acetylation. Oral bioavailability of hydralazine is dependent upon acetylator phenotype. Bioavailability is approximately 31% in slow acetylators and 10% in fast acetylators.
Volume of distribution Not Available
Protein binding 87%
Metabolism

Hydralazine, when administered orally, undergoes extensive first-pass metabolism by genetic polymorphic acetylation, which is responsible for a threefold range of oral bioavailability. Intravenously administered hydralazine does not undergo first-pass metabolism and, therefore, is not affected by acetylator phenotype. After the drug reaches the systemic circulation, it is combined with endogenous aldehydes and ketones, including pyruvic acid, to form hydrazone metabolites. The active metabolites, hydralazine acetonide hydrazone and hydralazine pyruvate hydrazone, are equipotent with the parent, hydralazine.
Route of elimination Hydralazine undergoes extensive hepatic metabolism; it is excreted mainly in the form of metabolites in the urine.
Half life 3 to 7 hours
Clearance Not Available
Toxicity Oral LD50 in rats: 173 and 187 mg/kg
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
  • Abraxis pharmaceutical products
  • Akorn inc
  • App pharmaceuticals llc
  • Luitpold pharmaceuticals inc
  • Smith and nephew solopak div smith and nephew
  • Solopak laboratories inc
  • Teva parenteral medicines inc
  • Teva pharmaceuticals usa inc
  • Actavis totowa llc
  • Ascot hosp pharmaceuticals inc div travenol laboratories inc
  • Glenmark pharmaceuticals ltd
  • Halsey drug co inc
  • Heritage pharmaceuticals inc
  • Hetero drugs ltd unit iii
  • Impax laboratories inc
  • Invagen pharmaceuticals inc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mutual pharmaceutical co inc
  • Par pharmaceutical inc
  • Pliva inc
  • Purepac pharmaceutical co
  • Quantum pharmics ltd
  • Sandoz inc
  • Superpharm corp
  • Tg united labs llc
  • Usl pharma inc
  • Vangard laboratories inc div midway medical co
  • Vitarine pharmaceuticals inc
  • Watson laboratories inc
  • West ward pharmaceutical corp
  • Zydus pharmaceuticals usa inc
Packagers
Dosage forms
Form Route Strength
Powder, for solution Intravenous
Tablet Oral
Prices
Unit description Cost Unit
Hydralazine 20 mg/ml vial 18.0 USD ml
Hydralazine 100 mg tablet 1.65 USD tablet
Hydralazine-HCTZ 50-50 mg capsule 1.2 USD capsule
HydrALAZINE HCl 100 mg tablet 1.05 USD tablet
Hydralazine-HCTZ 25-25 mg capsule 0.81 USD capsule
Hydralazine-HCTZ 100-50 mg capsule 0.75 USD capsule
HydrALAZINE HCl 50 mg tablet 0.67 USD tablet
Apresoline 50 mg tablet 0.65 USD tablet
HydrALAZINE HCl 25 mg tablet 0.53 USD tablet
HydrALAZINE HCl 10 mg tablet 0.47 USD tablet
Hydralazine 50 mg tablet 0.44 USD tablet
Hydralazine 25 mg tablet 0.35 USD tablet
Apo-Hydralazine 50 mg Tablet 0.29 USD tablet
Novo-Hylazin 50 mg Tablet 0.29 USD tablet
Apo-Hydralazine 25 mg Tablet 0.24 USD tablet
Hydralazine 10 mg tablet 0.22 USD tablet
Apo-Hydralazine 10 mg Tablet 0.11 USD tablet
Novo-Hylazin 10 mg Tablet 0.11 USD tablet
Patents Not Available
Properties
State solid
Melting point 172-173 oC
Experimental Properties
Property Value Source
logP 0.7 PhysProp
Predicted Properties
Property Value Source
water solubility 2.61e+00 g/l ALOGPS
logP 0.66 ALOGPS
logP 0.75 ChemAxon Molconvert
logS -1.79 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 4 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 63.83 ChemAxon Molconvert
rotatable bond count 1 ChemAxon Molconvert
refractivity 50.23 ChemAxon Molconvert
polarizability 16.06 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Kandler MR, Mah GT, Tejani AM, Stabler SN: Hydralazine for essential hypertension. Cochrane Database Syst Rev. 2010 Aug 4;8:CD004934. Pubmed
External Links
Resource Link
KEGG Drug D01302 Link_out
KEGG Compound C07040 Link_out
PubChem Compound 3637 Link_out
PubChem Substance 46507533 Link_out
ChemSpider 3511 Link_out
ChEBI 5775 Link_out
ChEMBL 5775 Link_out
Therapeutic Targets Database DAP000728 Link_out
PharmGKB PA449894 Link_out
Drug Product Database 441619 Link_out
RxList http://www.rxlist.com/cgi/generic/hydralazine.htm Link_out
Drugs.com http://www.drugs.com/cdi/hydralazine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Hydralazine Link_out
ATC Codes
  • C02DB02
  • C02DB01
AHFS Codes
  • 24:08.20
PDB Entries Not Available
FDA label Not Available
MSDS show (73.7 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Membrane copper amine oxidase

Pharmacological action: yes
Actions: inhibitor

Cell adhesion protein that participates in lymphocyte recirculation by mediating the binding of lymphocytes to peripheral lymph node vascular endothelial cells in an L-selectin- independent fashion. Has a monoamine oxidase activity

Organism class: human
UniProt ID: Q16853 Link_out
Gene: AOC3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Claud P, Padovani P, Guichard JP, Artur Y, Laine R: Involvement of semicarbazide-sensitive amine oxidase in tresperimus metabolism in human and in rat. Drug Metab Dispos. 2001 May;29(5):735-41. Pubmed
  2. Vidrio H, Medina M, Gonzalez-Romo P, Lorenzana-Jimenez M, Diaz-Arista P, Baeza A: Semicarbazide-sensitive amine oxidase substrates potentiate hydralazine hypotension: possible role of hydrogen peroxide. J Pharmacol Exp Ther. 2003 Nov;307(2):497-504. Epub 2003 Sep 11. Pubmed
  3. Vidrio H: Semicarbazide-sensitive amine oxidase: role in the vasculature and vasodilation after in situ inhibition. Auton Autacoid Pharmacol. 2003 Oct-Dec;23(5-6):275-83. Pubmed
  4. Vidrio H, Medina M: 2-bromoethylamine, a suicide inhibitor of semicarbazide-sensitive amine oxidase, increases hydralazine hypotension in rats. J Cardiovasc Pharmacol. 2005 Sep;46(3):316-24. Pubmed
  5. Vidrio H, Medina M: Hypotensive effect of hydroxylamine, an endogenous nitric oxide donor and SSAO inhibitor. J Neural Transm. 2007;114(6):863-5. Epub 2007 Mar 26. Pubmed
  6. Gronvall JL, Garpenstrand H, Oreland L, Ekblom J: An autoradiographic method of visualising semicarbazide-sensitive amine oxidase activity in mouse tissue sections. Neurobiology (Bp). 2000;8(2):167-77. Pubmed
  7. Gronvall JL, Garpenstrand H, Oreland L, Ekblom J: Autoradiographic imaging of formaldehyde adducts in mice: possible relevance for vascular damage in diabetes. Life Sci. 1998;63(9):759-68. Pubmed
  8. Lizcano JM, Fernandez de Arriba A, Tipton KF, Unzeta M: Inhibition of bovine lung semicarbazide-sensitive amine oxidase (SSAO) by some hydrazine derivatives. Biochem Pharmacol. 1996 Jul 26;52(2):187-95. Pubmed
  9. Lyles GA, McDougall SA: The enhanced daily excretion of urinary methylamine in rats treated with semicarbazide or hydralazine may be related to the inhibition of semicarbazide-sensitive amine oxidase activities. J Pharm Pharmacol. 1989 Feb;41(2):97-100. Pubmed
  10. Barrand MA, Callingham BA: The interaction of hydralazine with a semicarbazide-sensitive amine oxidase in brown adipose tissue of the rat. Its use as a radioactive ligand for the enzyme. Biochem J. 1985 Dec 1;232(2):415-23. Pubmed
  11. Barrand MA, Fox SA: Amine oxidase activities in brown adipose tissue of the rat: identification of semicarbazide-sensitive (clorgyline-resistant) activity at the fat cell membrane. J Pharm Pharmacol. 1984 Oct;36(10):652-8. Pubmed

2. Prolyl 4-hydroxylase subunit alpha-1

Pharmacological action: unknown
Actions: inhibitor

Catalyzes the posttranslational formation of 4- hydroxyproline in -Xaa-Pro-Gly- sequences in collagens and other proteins

Organism class: human
UniProt ID: P13674 Link_out
Gene: P4HA1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Knowles HJ, Tian YM, Mole DR, Harris AL: Novel mechanism of action for hydralazine: induction of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by inhibition of prolyl hydroxylases. Circ Res. 2004 Jul 23;95(2):162-9. Epub 2004 Jun 10. Pubmed
  3. Murad S, Tajima S, Pinnell SR: A paradoxical effect of hydralazine on prolyl and lysyl hydroxylase activities in cultured human skin fibroblasts. Arch Biochem Biophys. 1985 Sep;241(2):356-63. Pubmed# Chen KH, Paz MA, Gallop PM: Collagen prolyl hydroxylation in WI-
    38 fibroblast cultures: action of hydralazine. In Vitro. 1977 Jan;13(1):49-54. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Comments
Drug created on May 16, 2007 14:38 / Updated on April 19, 2011 15:09

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.