Guanethidine

Identification

Summary

Guanethidine is an antihypertensive agent used in the management of moderate and severe hypertension, either alone or as an adjunct, and for the management of renal hypertension.

Generic Name
Guanethidine
DrugBank Accession Number
DB01170
Background

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]

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 198.3085
Monoisotopic: 198.184446724
Chemical Formula
C10H22N4
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
  • Guanethidine
  • guanethidinum
  • guanetidina
  • Guanidine, (2-(hexahydro-1(2H)-azocinyl)ethyl)-
  • Heptamethylenimine, 1-(2-guanidinoethyl)-
  • N-(2-Perhydroazocin-1-ylethyl)guanidine

Pharmacology

Indication

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

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Contraindications & Blackbox Warnings
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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 (NE), rather than acting at the effector cell by inhibiting the association of norepinephrine with its receptors. It is taken up by norepinephrine transporters to be concentrated within the transmitter vesicles in place of NE, leading to gradual depletion of NE stores in the nerve endings. Guanethidine at the nerve terminal blocks the release of noradrenaline in response to 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
Humans
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
Adverse Effects
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Toxicity

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

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Guanethidine which could result in a higher serum level.
AbaloparatideAbaloparatide may increase the hypotensive activities of Guanethidine.
AcebutololGuanethidine may increase the hypotensive activities of Acebutolol.
AceclofenacThe therapeutic efficacy of Guanethidine can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Guanethidine can be decreased when used in combination with Acemetacin.
Food Interactions
  • Take with or without food. The absorption is unaffected by food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Guanethidine monosulfate5UBY8Y002G645-43-2YUFWAVFNITUSHI-UHFFFAOYSA-N
Guanethidine sulfate8AQ60474G960-02-6NBJGGHFXCGHTNJ-UHFFFAOYSA-N
International/Other Brands
Ismedine (Chen Ho)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Guanethidine 10 Tab 10mgTablet10 mg / tabOralPro Doc Limitee1984-12-311999-08-12Canada flag
IsmelinTablet25 mg/1OralNovartis1960-07-052008-07-31US flag
IsmelinTablet10 mg/1OralNovartis1960-07-052008-07-31US flag
Ismelin 25mgTablet25 mg / tabOralGeigy Pharmaceuticals, Ciba Geigy Canada Ltd.1960-12-311996-09-09Canada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Apo Guanethidine Sulfate Tab 10mgTablet10 mgOralApotex Corporation1977-12-312013-03-28Canada flag
Apo Guanethidine Sulfate Tab 25mgTablet25 mgOralApotex Corporation1977-12-312013-03-28Canada flag

Categories

ATC Codes
S01EX01 — GuanethidineC02CC02 — GuanethidineC02LF01 — Guanethidine and diuretics
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Aliphatic heteromonocyclic compound / Amine / Azacycle / Carboximidamide / Guanidine / Hydrocarbon derivative / Imine / Organoheterocyclic compound / Organopnictogen compound / Tertiary aliphatic amine
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
guanidines, azocanes (CHEBI:5557)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
ZTI6C33Q2Q
CAS number
55-65-2
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
N''-[2-(azocan-1-yl)ethyl]guanidine
SMILES
NC(N)=NCCN1CCCCCCC1

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
Human Metabolome Database
HMDB0015301
KEGG Drug
D02237
KEGG Compound
C07036
PubChem Compound
3518
PubChem Substance
46507567
ChemSpider
3398
BindingDB
50239969
RxNav
5036
ChEBI
5557
ChEMBL
CHEMBL765
ZINC
ZINC000001530648
Therapeutic Targets Database
DAP000124
PharmGKB
PA449823
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Guanethidine
MSDS
Download (74.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Novartis AG
  • Professional Co.
Dosage Forms
FormRouteStrength
TabletOral10 mg
TabletOral25 mg
TabletOral10 mg / tab
TabletOral10 mg/1
TabletOral25 mg/1
TabletOral25 mg / tab
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-MSsplash10-05dl-9800000000-92577f077502658eda15
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
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0002-1900000000-6b6c9a00456e64b283b2
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4j-0900000000-45beb9b99f0f13071bf8
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0btc-4900000000-35d2c06d5315c0587d77
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-6900000000-5a63f794fdef90c51438
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-01oy-5900000000-96e63240e29f90a1a219
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-000f-5900000000-b43200aefe3d6cea56bb
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-152.8716292
predicted
DarkChem Lite v0.1.0
[M-H]-148.9734
predicted
DeepCCS 1.0 (2019)
[M+H]+153.7240292
predicted
DarkChem Lite v0.1.0
[M+H]+151.80434
predicted
DeepCCS 1.0 (2019)
[M+Na]+153.4816292
predicted
DarkChem Lite v0.1.0
[M+Na]+160.22717
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
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. [Article]
  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. [Article]
  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. [Article]

Drug created at June 13, 2005 13:24 / Updated at December 02, 2023 07:00