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Identification
NameHydralazine
Accession NumberDB01275
Typesmall molecule
Groupsapproved
Description

A direct-acting vasodilator that is used as an antihypertensive agent. [PubChem]

Structure
Thumb
SynonymsNot Available
Salts
Name/CAS Structure Properties
Hydralazine hydrochloride
Thumb
  • InChI Key: ZUXNZUWOTSUBMN-UHFFFAOYSA-N
  • Monoisotopic Mass: 196.051574015
  • Average Mass: 196.637
DBSALT000792
Brand names
NameCompany
AlphapressAlphapharm
ApresolineNovartis
AprezinJohnson
Cesoline WPharmasant
Cesoline YPharmasant
DiazideThe Central
HidralBiocontrol
Hydralazine HydrochlorideSandoz
PressfallNisshin Seiyaku
SerpathiazideWashington
Brand mixtures
Brand NameIngredients
BiDilisosorbide dinitrate + hydralazine hydrochloride
CategoriesNot Available
CAS number86-54-4
WeightAverage: 160.1759
Monoisotopic: 160.074896276
Chemical FormulaC8H8N4
InChI KeyRPTUSVTUFVMDQK-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)
IUPAC Name
1-hydrazinylphthalazine
SMILES
NNC1=NN=CC2=CC=CC=C12
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassNaphthyridines
SubclassPhthalazines
Direct parentPhthalazines
Alternative parentsAminopyridazines; Benzene and Substituted Derivatives; Polyamines; Hydrazines and Derivatives
Substituentsaminopyridazine; pyridazine; benzene; polyamine; amine; hydrazine derivative; organonitrogen compound
Classification descriptionThis compound belongs to the phthalazines. These are compounds containing a phthalazine moiety, which consists of a benzene ring fused to a pyridazine, forming a 2,3-benzodiazine skeleton.
Pharmacology
IndicationFor 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.
PharmacodynamicsA 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 actionAlthough 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.
AbsorptionHydralazine 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 distributionNot Available
Protein binding87%
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.

SubstrateEnzymesProduct
Hydralazine
Not Available
Hydralazine acetone hydrazoneDetails
Hydralazine
Not Available
Hydralazine pyruvate hydrazoneDetails
Route of eliminationHydralazine undergoes extensive hepatic metabolism; it is excreted mainly in the form of metabolites in the urine.
Half life3 to 7 hours
ClearanceNot Available
ToxicityOral LD50 in rats: 173 and 187 mg/kg
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9854
Blood Brain Barrier + 0.9487
Caco-2 permeable + 0.8867
P-glycoprotein substrate Non-substrate 0.686
P-glycoprotein inhibitor I Non-inhibitor 0.9478
P-glycoprotein inhibitor II Non-inhibitor 0.9826
Renal organic cation transporter Non-inhibitor 0.8279
CYP450 2C9 substrate Non-substrate 0.8971
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.7467
CYP450 1A2 substrate Inhibitor 0.9106
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Inhibitor 0.526
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5294
Ames test AMES toxic 0.9107
Carcinogenicity Non-carcinogens 0.7719
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 3.2187 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9253
hERG inhibition (predictor II) Non-inhibitor 0.8589
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
FormRouteStrength
Powder, for solutionIntravenous
TabletOral
Prices
Unit descriptionCostUnit
Hydralazine 20 mg/ml vial18.0USDml
Hydralazine 100 mg tablet1.65USDtablet
Hydralazine-HCTZ 50-50 mg capsule1.2USDcapsule
HydrALAZINE HCl 100 mg tablet1.05USDtablet
Hydralazine-HCTZ 25-25 mg capsule0.81USDcapsule
Hydralazine-HCTZ 100-50 mg capsule0.75USDcapsule
HydrALAZINE HCl 50 mg tablet0.67USDtablet
Apresoline 50 mg tablet0.65USDtablet
HydrALAZINE HCl 25 mg tablet0.53USDtablet
HydrALAZINE HCl 10 mg tablet0.47USDtablet
Hydralazine 50 mg tablet0.44USDtablet
Hydralazine 25 mg tablet0.35USDtablet
Apo-Hydralazine 50 mg Tablet0.29USDtablet
Novo-Hylazin 50 mg Tablet0.29USDtablet
Apo-Hydralazine 25 mg Tablet0.24USDtablet
Hydralazine 10 mg tablet0.22USDtablet
Apo-Hydralazine 10 mg Tablet0.11USDtablet
Novo-Hylazin 10 mg Tablet0.11USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point172-173 °CU.S. Patent 2,484,029.
logP1.00SANGSTER (1993)
Predicted Properties
PropertyValueSource
water solubility2.61e+00 g/lALOGPS
logP0.66ALOGPS
logP0.75ChemAxon
logS-1.8ALOGPS
pKa (strongest acidic)17.69ChemAxon
pKa (strongest basic)6.4ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count2ChemAxon
polar surface area63.83ChemAxon
rotatable bond count1ChemAxon
refractivity50.23ChemAxon
polarizability16.06ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

U.S. Patent 2,484,029.

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
ResourceLink
KEGG DrugD01302
KEGG CompoundC07040
PubChem Compound3637
PubChem Substance46507533
ChemSpider3511
ChEBI5775
ChEMBLCHEMBL276832
Therapeutic Targets DatabaseDAP000728
PharmGKBPA449894
Drug Product Database441619
RxListhttp://www.rxlist.com/cgi/generic/hydralazine.htm
Drugs.comhttp://www.drugs.com/cdi/hydralazine.html
WikipediaHydralazine
ATC CodesC02DB02C02DB01
AHFS Codes
  • 24:08.20
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(73.7 KB)
Interactions
Drug Interactions
Drug
MetoprololIncreased effect of both drugs
PropranololIncreased effect of both drugs
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Food InteractionsNot Available

Targets

1. Membrane primary amine oxidase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Membrane primary amine oxidase Q16853 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Prolyl 4-hydroxylase subunit alpha-1 P13674 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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
  2. Zhao XJ, Ishizaki T: Metabolic interactions of selected antimalarial and non-antimalarial drugs with the major pathway (3-hydroxylation) of quinine in human liver microsomes. Br J Clin Pharmacol. 1997 Nov;44(5):505-11. Pubmed

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Drug created on May 16, 2007 14:38 / Updated on April 28, 2014 17:56