Pinaverium

Identification

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Name

Pinaverium

Accession Number

DB09090

Type

Small Molecule

Groups

Approved

Description

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.

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Pinaverium (DB09090)

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Synonyms

Not Available

Product Ingredients

Ingredient	UNII	CAS	InChI Key
Pinaverium bromide	7SCF54H12J	53251-94-8	IKGXLCMLVINENI-UHFFFAOYSA-M

Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
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Dicetel	Tablet		Oral	Bgp Pharma Ulc	1999-07-05	Not applicable
Dicetel	Tablet		Oral	Bgp Pharma Ulc	1993-12-31	Not applicable

Additional Data Available

Application Number
Application Number
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Product Code
Product Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
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Apo-pinaverium	Tablet		Oral	Apotex Corporation	2018-09-13	Not applicable
Apo-pinaverium	Tablet		Oral	Apotex Corporation	2018-09-13	Not applicable

Additional Data Available

Application Number
Application Number
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Product Code
Product Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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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)

Categories

• Agents causing hyperkalemia
• Alimentary Tract and Metabolism
• Antiarrhythmic agents
• Autonomic Agents
• Bradycardia-Causing Agents
• Calcium Channel Blockers
• Calcium-Regulating Hormones and Agents
• Cardiovascular Agents
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Drugs for Functional Gastrointestinal Disorders
• Membrane Transport Modulators
• Miscellaneous GI Drugs
• Oxazines
• Parasympatholytics
• Peripheral Nervous System Agents
• Potential QTc-Prolonging Agents
• QTc Prolonging Agents
• Vasodilating Agents

UNII

U2368VVE7O

CAS number

59995-65-2

Weight

Average: 511.52
Monoisotopic: 510.221348

Chemical Formula

C₂₆H₄₁BrNO₄

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

Pharmacology

Indication

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

Associated Conditions

• Irritable Bowel Syndrome (IBS)
• Functional disorders of the biliary tract

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.

Target	Actions	Organism
AVoltage-dependent L-type calcium channel subunit alpha-1S	antagonist inhibitor	Humans

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Adverse Effects

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Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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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

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.

Affected organisms

Not Available

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.

• All Drugs
• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental

Drug	Interaction
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2,4-thiazolidinedione	The risk or severity of hypoglycemia can be increased when Pinaverium is combined with 2,4-thiazolidinedione.
Abafungin	The therapeutic efficacy of Abafungin can be increased when used in combination with Pinaverium.
Abexinostat	The risk or severity of QTc prolongation can be increased when Pinaverium is combined with Abexinostat.
Acarbose	The risk or severity of hypoglycemia can be increased when Pinaverium is combined with Acarbose.
Acebutolol	The risk or severity of QTc prolongation can be increased when Pinaverium is combined with Acebutolol.
Aceclofenac	The risk or severity of hyperkalemia can be increased when Aceclofenac is combined with Pinaverium.
Acemetacin	The risk or severity of hyperkalemia can be increased when Pinaverium is combined with Acemetacin.
Acepromazine	The risk or severity of hypotension can be increased when Acepromazine is combined with Pinaverium.
Aceprometazine	The risk or severity of QTc prolongation can be increased when Pinaverium is combined with Aceprometazine.
Acetohexamide	The risk or severity of hypoglycemia can be increased when Pinaverium is combined with Acetohexamide.

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Extended Description
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Severity
Severity
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Evidence Level
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Food Interactions

Not Available

References

General References

1. Christen MO: Action of pinaverium bromide, a calcium-antagonist, on gastrointestinal motility disorders. Gen Pharmacol. 1990;21(6):821-5. [PubMed:2177709]
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. [PubMed:1313732]
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. [PubMed:4052731]
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. [PubMed:25632806]
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. [PubMed:8201843]
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. [PubMed:8600700]
7. Itoh Z, Takahashi I: Inhibitory effect of pinaverium bromide on gastrointestinal contractile activity in conscious dogs. Arzneimittelforschung. 1981;31(9):1450-3. [PubMed:7197953]
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. [PubMed:19416978]
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]

External Links

PubChem Compound

40704

PubChem Substance

310265017

ChemSpider

37182

BindingDB

50101975

ChEBI

135811

ChEMBL

CHEMBL1909324

Wikipedia

Pinaverium

ATC Codes

A03AX04 — Pinaverium

• A03AX — Other drugs for functional gastrointestinal disorders
• A03A — DRUGS FOR FUNCTIONAL GASTROINTESTINAL DISORDERS
• A03 — DRUGS FOR FUNCTIONAL GASTROINTESTINAL DISORDERS
• A — ALIMENTARY TRACT AND METABOLISM

AHFS Codes

• 56:92.00 — Miscellaneous GI Drugs

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Diagnostic	Malignancies	1
4	Recruiting	Treatment	Sphincter of Oddi Dysfunction	1
Not Available	Active Not Recruiting	Treatment	Irritable Bowel Syndrome (IBS)	1
Not Available	Unknown Status	Treatment	Irritable Bowel Syndrome (IBS)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage forms

Form	Route	Strength
Tablet	Oral

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	152-158	Product monograph
water solubility	Slightly soluble	Product monograph

Predicted Properties

Property	Value	Source
Water Solubility	3.42e-06 mg/mL	ALOGPS
logP	3.71	ALOGPS
logP	0.67	ChemAxon
logS	-8.2	ALOGPS
pKa (Strongest Acidic)	17.16	ChemAxon
pKa (Strongest Basic)	-3.8	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	4	ChemAxon
Hydrogen Donor Count	0	ChemAxon
Polar Surface Area	36.92 Å2	ChemAxon
Rotatable Bond Count	10	ChemAxon
Refractivity	143.32 m3·mol-1	ChemAxon
Polarizability	54.41 Å3	ChemAxon
Number of Rings	4	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Taxonomy

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 / MorpholinesAryl bromides / Tetraalkylammonium salts / Oxacyclic compounds / Dialkyl ethers / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives / Organic salts / Organobromides / Organic cations

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Substituents

Aromatic monoterpenoid / Bicyclic monoterpenoid / Pinane monoterpenoid / Dimethoxybenzene / O-dimethoxybenzene / Phenoxy compound / Benzylamine / Anisole / Methoxybenzene / Phenol etherPhenylmethylamine / Alkyl aryl ether / Bromobenzene / Aralkylamine / Halobenzene / Aryl bromide / Aryl halide / Monocyclic benzene moiety / Morpholine / Oxazinane / Benzenoid / Quaternary ammonium salt / Tetraalkylammonium salt / Oxacycle / Azacycle / Dialkyl ether / Ether / Organoheterocyclic compound / Organonitrogen compound / Amine / Organic oxygen compound / Hydrocarbon derivative / Organooxygen compound / Organic nitrogen compound / Organic salt / Organobromide / Organopnictogen compound / Organohalogen compound / Organic cation / Aromatic heteropolycyclic compound

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Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

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Drug created on September 15, 2015 15:22 / Updated on November 15, 2019 02:02