Identification

Name
Guanethidine
Accession Number
DB01170  (APRD01007)
Type
Small Molecule
Groups
Approved
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
Product Ingredients
IngredientUNIICASInChI Key
Guanethidine monosulfate5UBY8Y002G645-43-2YUFWAVFNITUSHI-UHFFFAOYSA-N
Guanethidine sulfate8AQ60474G960-02-6NBJGGHFXCGHTNJ-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo Guanethidine Sulfate Tab 10mgTablet10 mgOralApotex Corporation1977-12-312013-03-28Canada
Apo Guanethidine Sulfate Tab 25mgTablet25 mgOralApotex Corporation1977-12-312013-03-28Canada
Guanethidine 10 Tab 10mgTablet10 mgOralPro Doc Limitee1984-12-311999-08-12Canada
IsmelinTablet25 mg/1OralNovartis1960-07-052008-07-31Us
IsmelinTablet10 mg/1OralNovartis1960-07-052008-07-31Us
Ismelin 25mgTablet25 mgOralGeigy Pharmaceuticals, Ciba Geigy Canada Ltd.1960-12-311996-09-09Canada
International/Other Brands
Ismedine (Chen Ho) / Ismelin (Amdipharm)
Categories
UNII
ZTI6C33Q2Q
CAS number
55-65-2
Weight
Average: 198.3085
Monoisotopic: 198.184446724
Chemical Formula
C10H22N4
InChI Key
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

Pharmacology

Indication

For the treatment of moderate and severe hypertension, either alone or as an adjunct, and for the treatment of renal hypertension.

Pharmacodynamics

High 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 action

Guanethidine 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.

TargetActionsOrganism
ASodium-dependent noradrenaline transporter
inducer
Human
Absorption

3-30% of oral dose (poor and highly variable)

Volume of distribution
Not Available
Protein binding
Not 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 elimination

Ismelin is converted by the liver to three metabolites, which are excreted in the urine.

Half life

1.5 days

Clearance
  • Renal cl=56 ml/min
Toxicity

Side effects include drowsiness, dizziness, tiredness or confusion. LD50=1000 mg/kg (mouse, oral)

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylamphetamineThe serum concentration of 2,5-Dimethoxy-4-ethylamphetamine can be decreased when it is combined with Guanethidine.
2,5-Dimethoxy-4-ethylthioamphetamineThe serum concentration of 2,5-Dimethoxy-4-ethylthioamphetamine can be decreased when it is combined with Guanethidine.
3,4-MethylenedioxyamphetamineThe serum concentration of 3,4-Methylenedioxyamphetamine can be decreased when it is combined with Guanethidine.
4-Bromo-2,5-dimethoxyamphetamineThe serum concentration of 4-Bromo-2,5-dimethoxyamphetamine can be decreased when it is combined with Guanethidine.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypotensive activities of Guanethidine.
AcebutololGuanethidine may increase the hypotensive activities of Acebutolol.
AcemetacinThe therapeutic efficacy of Guanethidine can be decreased when used in combination with Acemetacin.
AcetaminophenAcetaminophen may decrease the excretion rate of Guanethidine which could result in a higher serum level.
Acetylsalicylic acidThe therapeutic efficacy of Guanethidine can be decreased when used in combination with Acetylsalicylic acid.
AlbendazoleThe metabolism of Albendazole can be increased when combined with Guanethidine.
Food Interactions
  • Take without regard to meals.

References

Synthesis Reference

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

General References
Not Available
External Links
Human Metabolome Database
HMDB0015301
KEGG Drug
D02237
KEGG Compound
C07036
PubChem Compound
3518
PubChem Substance
46507567
ChemSpider
3398
ChEBI
5557
ChEMBL
CHEMBL765
Therapeutic Targets Database
DAP000124
PharmGKB
PA449823
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Guanethidine
ATC Codes
C02LF01 — Guanethidine and diureticsC02CC02 — GuanethidineS01EX01 — Guanethidine
MSDS
Download (74.5 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Novartis AG
  • Professional Co.
Dosage forms
FormRouteStrength
TabletOral10 mg
TabletOral25 mg
TabletOral10 mg/1
TabletOral25 mg/1
Prices
Unit descriptionCostUnit
Guanethidine monosulf powder102.0USD g
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)276-281U.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-2ALOGPS
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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-0002-0900000000-63bf143534cccc53e099
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-000g-3900000000-b0c1213301460e6159e2
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-000f-8900000000-a1d8b2ab68936ac02c48
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-007c-9200000000-091425f6c0c880a5afdd
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-0a4r-9000000000-3d40142c51842fbbf5fc

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Organic nitrogen compounds
Class
Organonitrogen compounds
Sub Class
Guanidines
Direct Parent
Guanidines
Alternative Parents
Trialkylamines / Carboximidamides / Azacyclic compounds / Organopnictogen compounds / Imines / Hydrocarbon derivatives
Substituents
Tertiary aliphatic amine / Tertiary amine / Guanidine / Azacycle / Organoheterocyclic compound / Carboximidamide / Organopnictogen compound / Hydrocarbon derivative / Imine / Amine
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
guanidines, azocanes (CHEBI:5557)

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
Uniprot Name
Sodium-dependent noradrenaline transporter
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
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]

Drug created on June 13, 2005 07:24 / Updated on September 25, 2018 03:12