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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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Guanethidine Monosulfate
  • Guanethidine Sulphae
Brand names
  • Abapresin
  • Apo-Guanethidine
  • Eutensol
  • Ismelin
  • Oktadin
Brand name mixtures Not Available
Categories
  • Antihypertensive Agents
  • Adrenergic Agents
  • Sympatholytics
CAS number 645-43-2
Weight Average: 198.3085
Monoisotopic: 198.184446724
Chemical Formula C10H22N4
InChI Key InChIKey=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)
Plain Text
IUPAC Name
2-[2-(azocan-1-yl)ethyl]guanidine
SMILES
NC(N)=NCCN1CCCCCCC1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Aliphatic and Aryl Amines
  • Guanidines
  • Carboxamidines
Substructures
  • Aliphatic and Aryl Amines
  • Heterocyclic compounds
  • Guanidines
  • Carboxamidines
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.
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
Pharmacoeconomics
Manufacturers
  • Watson laboratories inc
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Guanethidine monosulf powder 102.0 USD g
Patents Not Available
Properties
State solid
Melting point 250 oC (sulfate salt)
Experimental Properties
Property Value Source
water solubility Very soluble PhysProp
logP 0.8 PhysProp
Predicted Properties
Property Value Source
water solubility 2.25e+00 g/l ALOGPS
logP 0.89 ALOGPS
logP 0.74 ChemAxon Molconvert
logS -1.95 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 4 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 67.64 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 59.70 ChemAxon Molconvert
polarizability 23.59 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D02237 Link_out
PubChem Compound 3518 Link_out
PubChem Substance 46507567 Link_out
ChemSpider 3398 Link_out
ChEBI 5557 Link_out
ChEMBL 5557 Link_out
Therapeutic Targets Database DAP000124 Link_out
PharmGKB PA449824 Link_out
Drug Product Database 0 Link_out
RxList http://www.rxlist.com/cgi/generic3/guanethidine.htm Link_out
Drugs.com http://www.drugs.com/mtm/guanethidine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Guanethidine Link_out
ATC Codes
  • C02CC02
  • S01EX01
AHFS Codes
  • 24:08.32
PDB Entries Not Available
FDA label Not Available
MSDS show (74.5 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Take without regard to meals.
Targets

1. Sodium-dependent noradrenaline transporter

Pharmacological action: yes
Actions: inducer

Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals

Organism class: human
UniProt ID: P23975 Link_out
Gene: SLC6A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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
  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
Enzymes

1. Cytochrome P450 3A4

Actions: inducer

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 xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:08

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.