Identification

Summary

Pinaverium is a spasmolytic agent used for the symptomatic treatment of irritable bowel syndrome (IBS) and functional disorders of the biliary tract.

Brand Names
Dicetel
Generic Name
Pinaverium
DrugBank Accession Number
DB09090
Background

Pinaverium is a spasmolytic agent used for functional gastrointestinal disorders. It is a quaternary ammonium compound that acts as an atypical calcium antagonist to restore normal bowel function. It is shown to relieve GI spasm and pain, transit disturbances and other symptoms related to motility disorders 1 and may be considered as effective first-lline therapy for patients with irritable bowel syndrome (IBS) 5. Pinaverium bromide is the common ingredient in formulations, mostly as oral tablets. Although it is not a currently approved drug by the FDA, pinaverium is available in over 60 countries including Canada.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 511.52
Monoisotopic: 510.221348
Chemical Formula
C26H41BrNO4
Synonyms
Not Available

Pharmacology

Indication

Pinaverium is indicated for the symptomatic treatment of irritable bowel syndrome (IBS) and functional disorders of the biliary tract.

Pharmacology
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Associated Conditions
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Contraindications
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Pharmacodynamics

Pinaverium is a selective and specific voltage-dependent calcium channel blocker located on intestinal smooth muscle cells to inhibit calcium influx. It mediates various effects on the GI tract: it causes oesophageal, gastric and duodenal relaxation, relaxes the colon and intestines, inhibits colonic motility in response to food, hormonal or pharmacological stimuli, accelerates gastric emptying, and reduces contractions of the gallbladder and phasic contractions of sphincter of Oddi 10,5. At higher concentrations, pinaverium also exhibits very weak anticholinergic effects 10 but is not shown to display vasodilatory or anti-arrythmic actions 9.

Mechanism of action

Pinaverium interacts with the 1,4-dihydropyridine binding sites on voltage dependent L-type calcium channels located on GI smooth muscle cells in a competitve manner 2. The binding site is located in the alpha 1S subunit and pinaverium most likely antagonizes the action of calcium ions by stabilizing a non-conducting channel state 8. Pinaverium inhibits smooth muscle contractions of the GI tract by inhibiting inward calcium current and calcium influx. It is suggested that pinaverium may be able to bind to both closed or inactivates states of the calcium channel with similar affinity 9,1.

TargetActionsOrganism
AVoltage-dependent L-type calcium channel subunit alpha-1S
antagonist
inhibitor
Humans
Absorption

After oral administration, pinaverium is poorly absorbed (5-10%) followed by uptake by liver. Poor absorption is due to its highly polar quaternary ammonium group and high molecular weight 10, which limits extensive diffusion across all cell membranes and promotes its selectivity towards the gastrointestinal tracts []. Peak plasma concentration is reached within one hour after administration and the absolute oral bioavailability is reported to be less than 1%.

Volume of distribution

It is selectively distributed to the digestive tract due to poor absorption and marked hepatobiliary excretion 10.

Protein binding

Pinaverium is highly bound to human plasma proteins with the ratio of 97% 10.

Metabolism

Hepatic metabolism of pinaverium involves demethylation of one of the methoxy groups, hydroxylation of the norpinanyl ring and elimination of the benzyl group with subsequent opening of the morpholine ring 10.

Route of elimination

Pinaverium is predominantly eliminated into feces 10.

Half-life

The mean elimination half life is approximately 1.5 hours 10.

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Some minor GI-related adverse effects include epigastric pain and/or fullness, nausea, constipation, heartburn, distension, and diarrhoea. Other side effects are headache, dry mouth, drowsiness, vertigo and skin allergy. Oral LD50 in mice, rats and rabbits are 1531 mg/kg, 1145 mg/kg and 154 mg/kg, respectively 10. Pinaverium displays no teratogenic, mutagenic or carcinogenic potential.

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
AbametapirThe serum concentration of Pinaverium can be increased when it is combined with Abametapir.
AbirateroneThe metabolism of Pinaverium can be decreased when combined with Abiraterone.
AcarboseThe risk or severity of hypoglycemia can be increased when Pinaverium is combined with Acarbose.
AcebutololAcebutolol may increase the arrhythmogenic activities of Pinaverium.
AceclofenacThe risk or severity of hyperkalemia can be increased when Aceclofenac is combined with Pinaverium.
AcemetacinThe risk or severity of hyperkalemia can be increased when Pinaverium is combined with Acemetacin.
AcetohexamideThe risk or severity of hypoglycemia can be increased when Pinaverium is combined with Acetohexamide.
AcetyldigitoxinAcetyldigitoxin may increase the arrhythmogenic activities of Pinaverium.
Acetylsalicylic acidThe risk or severity of hyperkalemia can be increased when Acetylsalicylic acid is combined with Pinaverium.
AcrivastineThe risk or severity of QTc prolongation can be increased when Pinaverium is combined with Acrivastine.
Interactions
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Food Interactions
  • Take with a full glass of water.
  • Take with food. This helps prevent pinaverium from irritating the esophagus.

Products

Products2
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Product Ingredients
IngredientUNIICASInChI Key
Pinaverium bromide7SCF54H12J53251-94-8IKGXLCMLVINENI-UHFFFAOYSA-M
International/Other Brands
Alevian Duo (Takeda) / Blocafer (Liferpal, Mexico) / Delibs (CONMED, Taiwan) / Ilyang Dicetel (Ilyang) / Nulite (Dominguez, Argentina) / Pakab (Wermar, Mexico) / Pinar (ABL Pharma, Peru) / Pinaven (Johnson, Taiwan) / Pladuet (Interlab Pharmaceutica, Mexico) / Planex (Rimsa, Mexico) / Riginal (Royal Pharma, Chile) / Spascolon (Chemi ph, Egypt) / Spasmopinaver (GNP, Egypt) / Spastec (Swiss Pharm, Taiwan) / Sucam (Everest, Taiwan) / Zerpyco (Atlantis, Mexico)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DicetelTablet100 mgOralBgp Pharma Ulc1999-07-05Not applicableCanada flag
DicetelTablet50 mgOralBgp Pharma Ulc1993-12-31Not applicableCanada flag
PinaveriumTablet50 mgOralAa Pharma Inc2018-09-13Not applicableCanada flag
PinaveriumTablet100 mgOralAa Pharma Inc2018-09-13Not applicableCanada flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
ALEVIAN DUO ® CAPSULASPinaverium bromide (100 mg) + Simethicone (300 mg)Capsule, liquid filledOralBAXALTA COLOMBIA S.A.S.2011-05-03Not applicableColombia flag
DICETEL® DÚO CÁPSULA DURAPinaverium bromide (100 mg) + Dimethicone (491.803 mg)Capsule, coatedOral2020-03-10Not applicableColombia flag
DISPAX ® CAPSULAS DURAS CON CONTENIDO LIQUIDOPinaverium bromide (100 mg) + Simethicone (300 mg)Capsule, coatedOralC.I. FARMACAPSULAS S.A.S - PLANTA NO. 22016-11-16Not applicableColombia flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
DICETEL 50 MG FİLM KAPLI TABLET, 40 ADETPinaverium (50 mg)Tablet, film coatedOralABBOTT LABORATUARLARI İTHALAT İHRACAT VE TİC. LTD. ŞTİ.2020-08-14Not applicableTurkey flag
DICETEL 50 MG FİLM KAPLI TABLET, 80 ADETPinaverium (50 mg)Tablet, film coatedOralABBOTT LABORATUARLARI İTHALAT İHRACAT VE TİC. LTD. ŞTİ.2020-08-14Not applicableTurkey flag

Categories

ATC Codes
A03AX04 — Pinaverium
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as bicyclic monoterpenoids. These are monoterpenoids containing exactly 2 rings, which are fused to each other.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Prenol lipids
Sub Class
Monoterpenoids
Direct Parent
Bicyclic monoterpenoids
Alternative Parents
Aromatic monoterpenoids / Dimethoxybenzenes / Phenylmethylamines / Phenoxy compounds / Anisoles / Benzylamines / Alkyl aryl ethers / Aralkylamines / Bromobenzenes / Morpholines
show 10 more
Substituents
Alkyl aryl ether / Amine / Anisole / Aralkylamine / Aromatic heteropolycyclic compound / Aromatic monoterpenoid / Aryl bromide / Aryl halide / Azacycle / Benzenoid
show 30 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
U2368VVE7O
CAS number
59995-65-2
InChI Key
DDHUTBKXLWCZCO-UHFFFAOYSA-N
InChI
InChI=1S/C26H41BrNO4/c1-26(2)21-6-5-19(22(26)16-21)7-11-31-12-8-28(9-13-32-14-10-28)18-20-15-24(29-3)25(30-4)17-23(20)27/h15,17,19,21-22H,5-14,16,18H2,1-4H3/q+1
IUPAC Name
4-[(2-bromo-4,5-dimethoxyphenyl)methyl]-4-[2-(2-{6,6-dimethylbicyclo[3.1.1]heptan-2-yl}ethoxy)ethyl]morpholin-4-ium
SMILES
COC1=C(OC)C=C(C[N+]2(CCOCCC3CCC4CC3C4(C)C)CCOCC2)C(Br)=C1

References

General References
  1. Christen MO: Action of pinaverium bromide, a calcium-antagonist, on gastrointestinal motility disorders. Gen Pharmacol. 1990;21(6):821-5. [Article]
  2. Feron O, Wibo M, Christen MO, Godfraind T: Interaction of pinaverium (a quaternary ammonium compound) with 1,4-dihydropyridine binding sites in rat ileum smooth muscle. Br J Pharmacol. 1992 Feb;105(2):480-4. [Article]
  3. Baumgartner A, Drack E, Halter F, Scheurer U: Effects of pinaverium bromide and verapamil on the motility of the rat isolated colon. Br J Pharmacol. 1985 Sep;86(1):89-94. [Article]
  4. Zheng L, Lai Y, Lu W, Li B, Fan H, Yan Z, Gong C, Wan X, Wu J, Huang D, Wang Y, Mei Y, Li Z, Jiang Z, Liu X, Ye J, Yang Y, Huang H, Xiao J: Pinaverium Reduces Symptoms of Irritable Bowel Syndrome in a Multicenter, Randomized, Controlled Trial. Clin Gastroenterol Hepatol. 2015 Jul;13(7):1285-1292.e1. doi: 10.1016/j.cgh.2015.01.015. Epub 2015 Jan 26. [Article]
  5. Bobo MH, Magous R, Christen MO, Bali JP: Effect of pinaverium and other calcium channel blockers on contraction of isolated gastric antral smooth muscle cells caused by gastrointestinal hormones. Life Sci. 1994;54(25):1947-54. [Article]
  6. Awad R, Dibildox M, Ortiz F: Irritable bowel syndrome treatment using pinaverium bromide as a calcium channel blocker. A randomized double-blind placebo-controlled trial. Acta Gastroenterol Latinoam. 1995;25(3):137-44. [Article]
  7. Itoh Z, Takahashi I: Inhibitory effect of pinaverium bromide on gastrointestinal contractile activity in conscious dogs. Arzneimittelforschung. 1981;31(9):1450-3. [Article]
  8. Tikhonov DB, Zhorov BS: Structural model for dihydropyridine binding to L-type calcium channels. J Biol Chem. 2009 Jul 10;284(28):19006-17. doi: 10.1074/jbc.M109.011296. Epub 2009 May 5. [Article]
  9. Godfraind T, Govoni S, Paoletti R, Vanhoutte PM (2013). Calcium Antagonists: Pharmacology and Clinical Research (pp. 306-307). Springer Science & Business Media. [ISBN:940111725X]
  10. BGP Pharma ULC: DICETEL (Pinaverium Bromide) product monograph [Link]
PubChem Compound
40704
PubChem Substance
310265017
ChemSpider
37182
BindingDB
50101975
RxNav
33724
ChEBI
135811
ChEMBL
CHEMBL1909324
Wikipedia
Pinaverium_bromide

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedDiagnosticMalignancies1
4Unknown StatusTreatmentSphincter of Oddi Dysfunction1
Not AvailableUnknown StatusTreatmentIrritable Bowel Syndrome (IBS)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Capsule, liquid filledOral
TabletOral100 mg
Capsule
Tablet, film coatedOral
Tablet, coatedOral50 mg
TabletOral
TabletOral50 mg
Tablet, coatedOral
Tablet, film coatedOral100 mg
Capsule, coatedOral
Tablet, coatedOral100 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)152-158Product monograph
water solubilitySlightly solubleProduct monograph
Predicted Properties
PropertyValueSource
Water Solubility3.42e-06 mg/mLALOGPS
logP3.71ALOGPS
logP0.67ChemAxon
logS-8.2ALOGPS
pKa (Strongest Acidic)17.16ChemAxon
pKa (Strongest Basic)-3.8ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area36.92 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity143.32 m3·mol-1ChemAxon
Polarizability54.41 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1S
Uniprot ID
Q13698
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1S
Molecular Weight
212348.1 Da
References
  1. Tikhonov DB, Zhorov BS: Structural model for dihydropyridine binding to L-type calcium channels. J Biol Chem. 2009 Jul 10;284(28):19006-17. doi: 10.1074/jbc.M109.011296. Epub 2009 May 5. [Article]
  2. Feron O, Wibo M, Christen MO, Godfraind T: Interaction of pinaverium (a quaternary ammonium compound) with 1,4-dihydropyridine binding sites in rat ileum smooth muscle. Br J Pharmacol. 1992 Feb;105(2):480-4. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
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. Uesawa Y, Takeuchi T, Mohri K: Integrated analysis on the physicochemical properties of dihydropyridine calcium channel blockers in grapefruit juice interactions. Curr Pharm Biotechnol. 2012 Jul;13(9):1705-17. [Article]

Drug created at September 15, 2015 21:22 / Updated at October 26, 2021 21:40