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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
ApresolineNot Available
Brand mixtures
Brand NameIngredients
BiDilisosorbide dinitrate + hydralazine hydrochloride
CategoriesNot Available
CAS number86-54-4
WeightAverage: 160.1759
Monoisotopic: 160.074896276
Chemical FormulaC8H8N4
InChI KeyInChIKey=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)
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
    Hydralazine acetone hydrazoneDetails
    Hydralazine
      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 °CPhysProp
      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 ReferenceNot 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
      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

      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

      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

      Comments
      Drug created on May 16, 2007 14:38 / Updated on September 16, 2013 17:13