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Identification
NameGuanethidine
Accession NumberDB01170  (APRD01007)
TypeSmall Molecule
GroupsApproved
Description

An antihypertensive agent that acts by inhibiting selectively transmission in post-ganglionic adrenergic nerves. It is believed to act mainly by preventing the release of norepinephrine at nerve endings and causes depletion of norepinephrine in peripheral sympathetic nerve terminals as well as in tissues. [PubChem]

Structure
Thumb
Synonyms
(2-(hexahydro-1(2h)-azocinyl)ethyl)guanidine
(2-(Octahydro-1-azocinyl)ethyl)guanidine
2-(1-N,N-Heptamethyleneimino)ethylguanidine
2-(1'-Azacyclooctyl)ethylguanidine
Azocine, 1-(2-guanidinoethyl)octahydro-
guanéthidine
guanethidinum
guanetidina
Guanidine, (2-(hexahydro-1(2H)-azocinyl)ethyl)-
Heptamethylenimine, 1-(2-guanidinoethyl)-
N-(2-Perhydroazocin-1-ylethyl)guanidine
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Guanethidine 10 Tab 10mgtablet10 mgoralPro Doc Limitee1984-12-311999-08-12Canada
Ismelin 25mgtablet25 mgoralCiba Pharmaceuticals, Ciba Geigy Canada Ltd.1960-12-311996-09-09Canada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo Guanethidine Sulfate Tab 10mgtablet10 mgoralApotex Inc1977-12-312013-03-28Canada
Apo Guanethidine Sulfate Tab 25mgtablet25 mgoralApotex Inc1977-12-312013-03-28Canada
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
IsmedineChen Ho
IsmelinAmdipharm
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Guanethidine monosulfate
645-43-2
Thumb
  • InChI Key: YUFWAVFNITUSHI-UHFFFAOYSA-N
  • Monoisotopic Mass: 296.151826443
  • Average Mass: 296.39
DBSALT001071
Guanethidine sulfate
60-02-6
Thumb
  • InChI Key: NBJGGHFXCGHTNJ-UHFFFAOYSA-N
  • Monoisotopic Mass: 494.336273167
  • Average Mass: 494.7
DBSALT001861
Categories
UNIIZTI6C33Q2Q
CAS number55-65-2
WeightAverage: 198.3085
Monoisotopic: 198.184446724
Chemical FormulaC10H22N4
InChI KeyInChIKey=ACGDKVXYNVEAGU-UHFFFAOYSA-N
InChI
InChI=1S/C10H22N4/c11-10(12)13-6-9-14-7-4-2-1-3-5-8-14/h1-9H2,(H4,11,12,13)
IUPAC Name
2-[2-(azocan-1-yl)ethyl]guanidine
SMILES
NC(N)=NCCN1CCCCCCC1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as guanidines. These are compounds containing a guanidine moiety, with the general structure (R1R2N)(R3R4N)C=N-R5.
KingdomOrganic compounds
Super ClassOrganonitrogen compounds
ClassGuanidines
Sub ClassNot Available
Direct ParentGuanidines
Alternative Parents
Substituents
  • Tertiary aliphatic amine
  • Tertiary amine
  • Guanidine
  • Azacycle
  • Organoheterocyclic compound
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Carboximidamide
  • Hydrocarbon derivative
  • Amine
  • Aliphatic heteromonocyclic compound
Molecular FrameworkAliphatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of moderate and severe hypertension, either alone or as an adjunct, and for the treatment of renal hypertension.
PharmacodynamicsHigh blood pressure can cause the heart and arteries to not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. High blood pressure may also increase the risk of heart attacks. These problems may be less likely to occur if blood pressure is controlled. Guanethidine works by decreasing the heart rate and relaxing the blood vessels so that blood can flow more easily through the body, thereby reducing these risks. It is a postganglionic sympathetic nerve terminal blocker that prevents the release of norepinephrine from nerve terminals.
Mechanism of actionGuanethidine acts at the sympathetic neuroeffector junction by inhibiting or interfering with the release and/or distribution of norepinephrine, rather than acting at the effector cell by inhibiting the association of norepinephrine with its receptors. It is taken up by norepinephrine transporters. It becomes concentrated in NE transmitter vesicles, replacing NE in these vesicles. This leads to a gradual depletion of NE stores in the nerve endings. Once inside the terminal it blocks the release of noradrenaline in response to arrival of an action potential. In contrast to ganglionic blocking agents, Guanethidine suppresses equally the responses mediated by alpha-and beta-adrenergic receptors but does not produce parasympathetic blockade. Since sympathetic blockade results in modest decreases in peripheral resistance and cardiac output, Guanethidine lowers blood pressure in the supine position. It further reduces blood pressure by decreasing the degree of vasoconstriction that normally results from reflex sympathetic nervous activity upon assumption of the upright posture, thus reducing venous return and cardiac output more.
Related Articles
Absorption3-30% of oral dose (poor and highly variable)
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Guanethidine is converted by the liver to three metabolites, which are excreted in the urine. The metabolites are pharmacologically less active than the parent compound.

Route of eliminationIsmelin is converted by the liver to three metabolites, which are excreted in the urine.
Half life1.5 days
Clearance
  • Renal cl=56 ml/min
ToxicitySide effects include drowsiness, dizziness, tiredness or confusion. LD50=1000 mg/kg (mouse, oral)
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.945
Blood Brain Barrier+0.9015
Caco-2 permeable-0.5683
P-glycoprotein substrateSubstrate0.7743
P-glycoprotein inhibitor INon-inhibitor0.9342
P-glycoprotein inhibitor IIInhibitor0.5063
Renal organic cation transporterInhibitor0.7586
CYP450 2C9 substrateNon-substrate0.8981
CYP450 2D6 substrateSubstrate0.6426
CYP450 3A4 substrateNon-substrate0.7884
CYP450 1A2 substrateNon-inhibitor0.908
CYP450 2C9 inhibitorNon-inhibitor0.9363
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.939
CYP450 3A4 inhibitorNon-inhibitor0.9611
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9748
Ames testNon AMES toxic0.6626
CarcinogenicityNon-carcinogens0.9595
BiodegradationNot ready biodegradable0.9883
Rat acute toxicity2.4210 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6083
hERG inhibition (predictor II)Non-inhibitor0.8115
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Tabletoral10 mg
Tabletoral25 mg
Prices
Unit descriptionCostUnit
Guanethidine monosulf powder102.0USD g
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point276-281U.S. Patent 2,928,829 U.S. Patent 3,006,913 U.S. Patent 3,055,882
water solubilityVery solubleNot Available
logP0.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility2.25 mg/mLALOGPS
logP0.89ALOGPS
logP0.74ChemAxon
logS-1.9ALOGPS
pKa (Strongest Basic)11.77ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area67.64 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity59.7 m3·mol-1ChemAxon
Polarizability23.67 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

U.S. Patent 2,928,829
U.S. Patent 3,006,913
U.S. Patent 3,055,882

General ReferencesNot Available
External Links
ATC CodesC02CC02C02LF01S01EX01
AHFS Codes
  • 24:08.32
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (74.5 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inducer
General Function:
Norepinephrine:sodium symporter activity
Specific Function:
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name:
SLC6A2
Uniprot ID:
P23975
Molecular Weight:
69331.42 Da
References
  1. Joyce PI, Atcheson R, Marcus RJ, Heffernan AM, Rowbotham DJ, Lambert DG: Interaction of local anaesthetic agents with the endogenous norepinephrine transporter in SH-SY5Y human neuroblastoma cells. Neurosci Lett. 2001 Jun 15;305(3):161-4. [PubMed:11403930 ]
  2. Yi E, Love JA: Alpha-adrenergic modulation of synaptic transmission in rabbit pancreatic ganglia. Auton Neurosci. 2005 Oct 30;122(1-2):45-57. Epub 2005 Aug 25. [PubMed:16126010 ]
  3. Galli A, Blakely RD, DeFelice LJ: Norepinephrine transporters have channel modes of conduction. Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8671-6. [PubMed:8710929 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inducer
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
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 xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
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Drug created on June 13, 2005 07:24 / Updated on May 06, 2016 10:36