Pentaerythritol tetranitrate

Identification

Name
Pentaerythritol tetranitrate
Accession Number
DB06154
Type
Small Molecule
Groups
Approved
Description

Pentaerythritol tetranitrate is the nitrate ester of pentaerythritol that possesses explosive properties. When mixed with a plasticizer, this chemical forms a plastic explosive. It is recognized by the FDA to be a coronary vasodilator in the treatment of heart conditions such as angina [9].

It is a pentaerythritol nitrate in which all four hydroxy groups of pentaerythritol have been converted to the corresponding nitrate ester. It is a vasodilator with properties that are quite similar to those of glyceryl trinitrate, however, with a more prolonged duration of action. It is also one of the most powerful high explosives known and is a component of the plastic explosive known as Semtex [7].

PETN has the chemical formula C5H8N4O12. It is formed by reacting pentaerythritol (C5H12O4), an alcohol commonly used in paints and varnishes, with nitric acid (HNO2). The reacting solution is chilled to precipitate the PETN. It is then filtered out, washed, dried, and recrystallized to produce a colorless crystalline material that is stored and shipped as a mixture with water and alcohol [8].

Interestingly, this drug was studied for potential benefits in chronic ischemic heart failure patients. PETN targeting reactive oxygen species generation halted the changes of mitochondrial antioxidant enzymes and progressive fibrotic remodeling, leading to amelioration of cardiac functional performance in rats with ischemic heart failure [4].

Structure
Thumb
Synonyms
  • Corpent
  • PENT
  • PENTA
  • Pentaerithrityl tetranitrate
  • pentaerithrityli tetranitras
  • Pentaerythritol tetranitrate
  • Penthrite
  • TEN
  • Tetranitrate de pentaerithrityle
  • Tetranitrato de pentaeritritilo
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Peritrate Sa 80mg TabTablet, extended release80 mgOralParke Davis Division, Warner Lambert Canada Inc.1961-12-311998-09-14Canada
Peritrate Tab 10mgTablet10 mgOralParke Davis Division, Warner Lambert Canada Inc.1961-12-311997-08-11Canada
Peritrate Tab 20mgTablet20 mgOralParke Davis Division, Warner Lambert Canada Inc.1961-12-311998-09-14Canada
Categories
UNII
10L39TRG1Z
CAS number
78-11-5
Weight
Average: 316.1366
Monoisotopic: 316.01387174
Chemical Formula
C5H8N4O12
InChI Key
TZRXHJWUDPFEEY-UHFFFAOYSA-N
InChI
InChI=1S/C5H8N4O12/c10-6(11)18-1-5(2-19-7(12)13,3-20-8(14)15)4-21-9(16)17/h1-4H2
IUPAC Name
3-(nitrooxy)-2,2-bis[(nitrooxy)methyl]propyl nitrate
SMILES
[O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O

Pharmacology

Indication

Used for the treatment of angina pectoris [7].

Pharmacodynamics

Organic nitrate which causes systemic vasodilation, decreasing cardiovascular preload [15].

Nitrate enters vascular smooth muscle and converted to nitric oxide (NO) which acts as a cellular messenger, leading to activation of cyclic GMP and, therefore, vasodilation [15].

The nitrovasodilator group of drugs relaxes most smooth muscles in the body, including those in the walls of arteries and veins, and selectively dilate large coronary vessels [12]. Lower doses of nitrates increase coronary blood flow without significantly affecting systemic arterial pressure. Higher doses, especially if repeated frequently, decrease systolic and diastolic blood pressure as well as cardiac output, which can result in a headache, weakness, dizziness, and the activation of compensatory sympathetic reflexes, including tachycardia and peripheral arteriolar vasoconstriction [5].

Smooth muscles in the bronchi, biliary tract, gastrointestinal tract, ureters, and uterus also can be relaxed by nitrovasodilators. PETN seems to be unique among the long-acting nitrovasodilators in that patients do not demonstrate tolerance to treatment, which results in sustained vasodilation in humans with continuous PETN treatment [14].

Important to note is that this drug is devoid of induction of oxidative stress and related side-effects such as endothelial dysfunction or tolerance to nitrates. Some of these effects are related to special pharmacokinetics of PETN, but upon chronic administration, PETN also induces antioxidative pathways at the genomic level, resulting in increased expression of heme oxygenase-1 (HO-1) and ferritin, both possessing highly protective properties. There is good experimental evidence that at least part of the beneficial profile of long-term treatment with this drug is based on the activation of the heme oxygenase-1/ferritin system [16].

Mechanism of action

Pentaerythritol tetranitrate is the lipid soluble polyol ester of nitric acid belonging to the family of nitro-vasodilators. Pentaerythritol tetranitrate releases free nitric oxide (NO) after the denitration reaction, which triggers NO-dependent signaling transduction involving soluble guanylate cyclase (sGC). Nitric oxide binds reversibly to the ferrous-heme center of sGC, causing conformational change and activating the enzyme. This enzyme activation results in increased cellular concentrations of _cyclic guanosine monophosphate _(cGMP) within the vascular smooth muscle, resulting in vasodilation mediated by cGMP-dependent protein kinases. Additionally, this agent causes dose-dependent arterial and venous bed [7].

TargetActionsOrganism
AHemoglobin subunit alpha
agonist
Human
AHemoglobin subunit beta
agonist
Human
NFree radicals
antagonist
Human
Absorption
Not Available
Volume of distribution

The steady-state volume of distribution was 4.2 +/- 1.1 L/kg (n = 6) in rats given this drug by the intra-arterial route [1].

Protein binding
Not Available
Metabolism

Extensively metabolized in the liver [15].

Metabolites: pentaerythritol trinitrate, pentaerythritol dinitrate, pentaerythritol mononitrate, & pentaerythritol (inactive)[15]

Route of elimination

Mainly the urine [15].

Half life

The elimination half-life in plasma from male volunteers given an oral 100-mg dose of the tetranitrate was reported to be 4-5 hours [9].

Clearance

In a pharmacokinetic study of rats after intra-arterial administration of this drug, the clearance was measured to be 0.61 +/- 0.16 L/min/kg [1].

Toxicity

The toxicity of nitrate drugs are the result of nitrate conversion to nitrite in the body. Nitrite leads to the autocatalytic oxidation of oxyhemoglobin to both hydrogen peroxide and methemoglobin. This increase in methemoglobin levels is a condition known as methemoglobinemia and is manifested by tissue hypoxia, as methemoglobin is unable to bind oxygen [17].

Dizziness, redness of the skin (due to vasodilatation), skin irritation and headache are common adverse effects of this drug. Postural hypotension can also occur, especially if this drug is taken at higher doses or while standing [9].

PETN - Oral LD50 (mouse) = 25,000 mg/kg [MSDS]

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

Interactions

Drug Interactions
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Pentaerythritol Tetranitrate which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Pentaerythritol Tetranitrate which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Pentaerythritol Tetranitrate which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Pentaerythritol Tetranitrate which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Pentaerythritol Tetranitrate which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Pentaerythritol Tetranitrate which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Pentaerythritol Tetranitrate which could result in a higher serum level.
AclidiniumPentaerythritol Tetranitrate may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastinePentaerythritol Tetranitrate may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Pentaerythritol Tetranitrate which could result in a higher serum level.
Food Interactions
  • Take without regard to meals, taking it with food will dealy the onset on action.

References

General References
  1. King SY, Fung HL: Pharmacokinetics of pentaerythritol tetranitrate following intra-arterial and oral dosing in the rat. J Pharm Sci. 1986 Mar;75(3):247-50. [PubMed:3701607]
  2. Jurt U, Gori T, Ravandi A, Babaei S, Zeman P, Parker JD: Differential effects of pentaerythritol tetranitrate and nitroglycerin on the development of tolerance and evidence of lipid peroxidation: a human in vivo study. J Am Coll Cardiol. 2001 Sep;38(3):854-9. [PubMed:11527645]
  3. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [PubMed:23611293]
  4. Fraccarollo D, Galuppo P, Neuser J, Bauersachs J, Widder JD: Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure. Hypertension. 2015 Nov;66(5):978-87. doi: 10.1161/HYPERTENSIONAHA.115.05931. Epub 2015 Sep 8. [PubMed:26351025]
  5. Abrams J: Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J. 1985 Jul;110(1 Pt 2):216-24. [PubMed:3925741]
  6. Pentaerythritol tetranitrate [Link]
  7. CheBi - Pentaerythritol [Link]
  8. PETN [Link]
  9. OSHA document [Link]
  10. Pentaerythritol tetra nitrate [Link]
  11. Determination of Pentaerythritol Tetranitrate in Pharmaceuticals by High Performance Liquid Chromatography [Link]
  12. Pentaerythrityl tetranitrate (PETN): a better nitrate? [Link]
  13. Pentaerythritol tetranitrate [Link]
  14. Pentaerythritol tetranitrate [Link]
  15. Medscape- Pentaerythritol tetra nitrate [Link]
  16. Characterization of the Antioxidant Properties of Pentaerithrityl Tetranitrate (PETN)-Induction of the Intrinsic Antioxidative System Heme Oxygenase-1 (HO-1) [Link]
  17. Pentaerythritol tetranitrate [Link]
  18. Pentaerythritoltetranitrate (PETN) EPA document [Link]
  19. PENTAERYTHRITE TETRANITRATE [Link]
  20. Pentaerithrityl tetranitrate improves angiotensin II induced vascular dysfunction via induction of heme oxygenase-1 [Link]
External Links
KEGG Drug
D01721
PubChem Compound
6518
PubChem Substance
347827759
ChemSpider
6271
ChEBI
25879
ChEMBL
CHEMBL466659
Wikipedia
Pentaerythritol_tetranitrate
ATC Codes
C01DA05 — Pentaerithrityl tetranitrateC01DA55 — Pentaerithrityl tetranitrate, combinations
MSDS
Download (40.9 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
Not AvailableRecruitingDiagnosticAdequate Vitamin A Store / Healthy Infants / High Vitamin A Store / Infants With an Inflammatory Condition / Inflammatory Reaction1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, extended releaseOral80 mg
TabletOral10 mg
TabletOral20 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)140MSDS
water solubility0.133 mg/mLL2402
Predicted Properties
PropertyValueSource
Water Solubility0.133 mg/mLALOGPS
logP1.62ALOGPS
logP0.055ChemAxon
logS-3.4ALOGPS
pKa (Strongest Basic)-5.5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area209.48 Å2ChemAxon
Rotatable Bond Count12ChemAxon
Refractivity54.49 m3·mol-1ChemAxon
Polarizability22.79 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Mass Spectrum (Electron Ionization)MSsplash10-004j-9000000000-14fe59ae096adb8f0c17
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

Taxonomy

Description
This compound belongs to the class of organic compounds known as alkyl nitrates. These are organic compounds containing a nitrate that is O-linked to an alkyl group.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organic oxoanionic compounds
Sub Class
Organic nitrates
Direct Parent
Alkyl nitrates
Alternative Parents
Organic nitro compounds / Organic nitric acids and derivatives / Organooxygen compounds / Organic oxides / Organic nitrogen compounds / Hydrocarbon derivatives
Substituents
Alkyl nitrate / Organic nitro compound / Organic nitric acid or derivatives / Organic 1,3-dipolar compound / Allyl-type 1,3-dipolar organic compound / Organic nitrogen compound / Organic oxide / Hydrocarbon derivative / Organooxygen compound / Aliphatic acyclic compound
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
pentaerythritol nitrate (CHEBI:25879)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Oxygen transporter activity
Specific Function
Involved in oxygen transport from the lung to the various peripheral tissues.
Gene Name
HBA1
Uniprot ID
P69905
Uniprot Name
Hemoglobin subunit alpha
Molecular Weight
15257.405 Da
References
  1. Pentaerythritol tetranitrate [Link]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Oxygen transporter activity
Specific Function
Involved in oxygen transport from the lung to the various peripheral tissues.LVV-hemorphin-7 potentiates the activity of bradykinin, causing a decrease in blood pressure.Spinorphin: functions as an...
Gene Name
HBB
Uniprot ID
P68871
Uniprot Name
Hemoglobin subunit beta
Molecular Weight
15998.34 Da
References
  1. Pentaerythritol tetranitrate [Link]
3. Free radicals
Kind
Group
Organism
Human
Pharmacological action
No
Actions
Antagonist
References
  1. Fraccarollo D, Galuppo P, Neuser J, Bauersachs J, Widder JD: Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure. Hypertension. 2015 Nov;66(5):978-87. doi: 10.1161/HYPERTENSIONAHA.115.05931. Epub 2015 Sep 8. [PubMed:26351025]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inducer
General Function
Heme binding
Specific Function
Has guanylyl cyclase on binding to the beta-1 subunit.Isoform 2 acts as a negative regulator of guanylyl cyclase activity as it forms non-functional heterodimers with the beta subunits.
Gene Name
GUCY1A2
Uniprot ID
P33402
Uniprot Name
Guanylate cyclase soluble subunit alpha-2
Molecular Weight
81749.185 Da
References
  1. Pentaerythritol tetranitrate [Link]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inducer
General Function
Tetrahydrobiopterin binding
Specific Function
Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induce...
Gene Name
NOS3
Uniprot ID
P29474
Uniprot Name
Nitric oxide synthase, endothelial
Molecular Weight
133287.62 Da
References
  1. CheBi - Pentaerythritol [Link]
  2. Nitrate Reduction to Nitrite, Nitric Oxide and Ammonia by Gut Bacteria under Physiological Conditions [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Electron carrier activity
Specific Function
Not Available
Gene Name
ALDH2
Uniprot ID
P05091
Uniprot Name
Aldehyde dehydrogenase, mitochondrial
Molecular Weight
56380.93 Da
References
  1. OSHA document [Link]

Drug created on January 30, 2008 07:45 / Updated on December 14, 2018 15:52