Identification

Summary

Drotaverine is a phosphodiesterase-4 inhibitor used to alleviate gastrointestinal and genitourinary smooth muscle spasms.

Generic Name
Drotaverine
DrugBank Accession Number
DB06751
Background

Drotaverine is an antispasmodic drug that works by inhibiting phosphodiesterase-4 (PDE4).5 It is a benzylisoquinoline derivative that is structurally related to papaverine, although it displays more potent antispasmodic activities than papaverine. Drotaverine has been used in the symptomatic treatment of various spastic conditions, such as gastrointestinal diseases, biliary dyskinesia, and vasomotor diseases associated with smooth muscle spasms.1 It also has been investigated in dysmenorrhea, abortion, 3 and augmentation of labour.4 More recently, drotaverine gained attention in the treatment of benign prostatic hyperplasia, parainfluenza, and avian influenza viruses.5

Drotaverine is not approved by the FDA, European Medicines Agency, or Health Canada. It is approved for use in Thailand as oral tablets or intramuscular injections.9

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 397.5072
Monoisotopic: 397.225308485
Chemical Formula
C24H31NO4
Synonyms
  • Drotaverin
  • Drotaverina
  • Drotaverine
  • Drotaverinum

Pharmacology

Indication

Drotaverine is used to alleviate gastrointestinal and genitourinary smooth muscle spasms, such as cholecystitis and gallbladder disorders.9

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Drotaverine is an e spasmolytic agent with a relaxing effect on smooth muscles. It works to relieve visceral spasms and improve cervical dilation. In vitro, drotaverine mediated cytostatic effects on several human tumor cell lines and nonmalignant mouse fibroblasts.5 Drotaverine may have minor allosteric calcium channel blocking properties: in vitro, drotaverine behaves like voltage-dependent L-type calcium channel blockers.[A231624]

Mechanism of action

Drotaverine is a selective inhibitor of phosphodiesterase 4 (PDE4), which is an enzyme responsible for the degradation of cyclic adenosine monophosphate (cAMP). Inhibition of PDE4 leads to elevated levels of cAMP, leading to smooth muscle relaxation. Recent research showed that low levels of cAMP have been associated with brain tumorigenesis, leading to the investigation of PDE4 inhibitors as potential anticancer agents.5

TargetActionsOrganism
AcAMP-specific 3',5'-cyclic phosphodiesterase 4A
inhibitor
Humans
UVoltage-dependent L-type calcium channel
inhibitor
Humans
Absorption

Drotaverine is not completely absorbed following oral administration and its bioavailability is highly variable. Following oral administration of a single 80 mg dose, the absolute bioavailability ranged between 24.5 and 91 % with a mean of 58.2 ± 18.2%. Mean Cmax was 292 ± 88 ng/mL. Mean AUC was 3251 ± 950 ng*h/mL. Mean Tmax was 1.9 ± 0.54 hours.1

Volume of distribution

Following oral administration of a single 80 mg dose, the mean volume of distribution was 193 ± 48 L. Following an intravenous dose of 80 mg, the mean volume of distribution was 195 ± 48 L.1

Protein binding

There is no information available.

Metabolism

Drotaverine is reported to undergo extensive hepatic metabolism, which is its main route of elimination. It may also undergo biliary excretion to form conjugated metabolites.1 Proposed metabolic pathways and metabolites are based on limited animal studies: in rats, the major identified metabolites of drotaverine are 4'-desethyl-drotaverine, 6-desethyl-drotaverine, drotaveraldine, and 4'-desethyl-drotaveraldine, all of which are glucuronidated in the bile. 4'-desethyl-drotaveraldine was the most predominant metabolite eliminated into the bile.6

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Route of elimination

Drotaverine is mainly eliminated via hepatic metabolism.1 About 67% of the drug is found in feces and 20% of the drug was eliminated with urine.7

Half-life

Following oral administration of a single 80 mg dose, the mean half-life was 9.11 ± 1.29 hours. Following an intravenous dose of 80 mg, the mean half-life 9.33 ± 1.02 hours.1

Clearance

Following oral administration of a single 80 mg dose, the mean renal clearance was 0.59 ± 0.18 mL/min. Following an intravenous dose of 80 mg, the mean renal clearance was 0.73 ± 0.29 mL/min.1

Adverse Effects
Adverseeffects
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Toxicity

Oral LD50 is 540 mg/kg in rats and 350 mg/kg in mice.8 There is limited information on drotaverine overdose and toxicity.

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
Isosorbide mononitrateDrotaverine may increase the vasodilatory activities of Isosorbide mononitrate.
Patent BlueThe therapeutic efficacy of Drotaverine can be decreased when used in combination with Patent Blue.
RiociguatDrotaverine may increase the hypotensive activities of Riociguat.
Interactions
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Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Drotaverine hydrochloride24ZVH4C669985-12-6JBFLYOLJRKJYNV-MASIZSFYSA-N
International/Other Brands
Drotin / No-Spa (Sanofi-Aventis) / Taverin

Categories

ATC Codes
A03AD02 — Drotaverine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as tetrahydroisoquinolines. These are tetrahydrogenated isoquinoline derivatives.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Tetrahydroisoquinolines
Sub Class
Not Available
Direct Parent
Tetrahydroisoquinolines
Alternative Parents
Phenoxy compounds / Phenol ethers / Aralkylamines / Alkyl aryl ethers / Enamines / Dialkylamines / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Alkyl aryl ether / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Enamine / Ether / Hydrocarbon derivative / Monocyclic benzene moiety
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
98QS4N58TW
CAS number
14009-24-6
InChI Key
OMFNSKIUKYOYRG-MOSHPQCFSA-N
InChI
InChI=1S/C24H31NO4/c1-5-26-21-10-9-17(14-22(21)27-6-2)13-20-19-16-24(29-8-4)23(28-7-3)15-18(19)11-12-25-20/h9-10,13-16,25H,5-8,11-12H2,1-4H3/b20-13-
IUPAC Name
(1Z)-1-[(3,4-diethoxyphenyl)methylidene]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline
SMILES
CCOC1=C(OCC)C=C(\C=C2/NCCC3=CC(OCC)=C(OCC)C=C23)C=C1

References

General References
  1. Bolaji OO, Onyeji CO, Ogundaini AO, Olugbade TA, Ogunbona FA: Pharmacokinetics and bioavailability of drotaverine in humans. Eur J Drug Metab Pharmacokinet. 1996 Jul-Sep;21(3):217-21. [Article]
  2. Rai RR, Dwivedi M, Kumar N: Efficacy and safety of drotaverine hydrochloride in irritable bowel syndrome: a randomized double-blind placebo-controlled study. Saudi J Gastroenterol. 2014 Nov-Dec;20(6):378-82. doi: 10.4103/1319-3767.145331. [Article]
  3. Tomaszewski D, Balkota M: Intramuscular Administration of Drotaverine Hydrochloride Decreases Both Incidence of Urinary Retention and Time to Micturition in Orthopedic Patients under Spinal Anesthesia: A Single Blinded Randomized Study. Biomed Res Int. 2015;2015:926953. doi: 10.1155/2015/926953. Epub 2015 Jun 21. [Article]
  4. Madhu C, Mahavarkar S, Bhave S: A randomised controlled study comparing Drotaverine hydrochloride and Valethamate bromide in the augmentation of labour. Arch Gynecol Obstet. 2010 Jul;282(1):11-5. doi: 10.1007/s00404-009-1188-8. Epub 2009 Jul 31. [Article]
  5. Pavel IZ, Heller L, Sommerwerk S, Loesche A, Al-Harrasi A, Csuk R: Drotaverine - a Concealed Cytostatic! Arch Pharm (Weinheim). 2017 Jan;350(1). doi: 10.1002/ardp.201600289. Epub 2016 Nov 23. [Article]
  6. Vargay Z, Simon G, Winter M, Szuts T: Qualitative and quantitative determination of drotaverine metabolites in rat bile. Eur J Drug Metab Pharmacokinet. 1980;5(2):69-74. doi: 10.1007/BF03189448. [Article]
  7. Magyar K, Lengyel M, Knoll J: Absorption, distribution and elimination of drotaverine. Acta Physiol Acad Sci Hung. 1978;51(4):401-11. [Article]
  8. Cayman Chemical: Drotaverine Safety Data Sheet [Link]
  9. FDA Thailand: Spablock (Drotaverine) Oral Tablet [Link]
Human Metabolome Database
HMDB0015669
PubChem Compound
1712095
PubChem Substance
99443287
ChemSpider
1361582
BindingDB
50237620
RxNav
23684
ChEBI
135630
ChEMBL
CHEMBL551978
ZINC
ZINC000100011979
PharmGKB
PA165958398
Wikipedia
Drotaverine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4TerminatedTreatmentMenstrual Distress (Dysmenorrhea)1
3CompletedPreventionBile Duct Diseases / ERCP / Pancreatic Diseases1
2Unknown StatusDiagnosticEffect of Meperidine or Drotaverine on Effacement and Dilatation of the Cervix During Labor in Full Term Primigravidae1
2, 3CompletedTreatmentFailure of Cervical Dilation as Antepartum Condition / Mild Birth Asphyxia, APGAR 4-7 / Pain, Labor / Prolonged First Stage of Labor1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solution20 mg/1ml
TabletOral
TabletOral40 mg
Tablet, coatedOral40 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)197https://datasheets.scbt.com/sds/aghs/en/sc-211384.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.002 mg/mLALOGPS
logP5.35ALOGPS
logP4.19ChemAxon
logS-5.3ALOGPS
pKa (Strongest Basic)7.4ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area48.95 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity117.99 m3·mol-1ChemAxon
Polarizability46.99 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9958
Blood Brain Barrier+0.753
Caco-2 permeable+0.6023
P-glycoprotein substrateSubstrate0.8447
P-glycoprotein inhibitor IInhibitor0.7972
P-glycoprotein inhibitor IINon-inhibitor0.8544
Renal organic cation transporterNon-inhibitor0.625
CYP450 2C9 substrateNon-substrate0.7958
CYP450 2D6 substrateNon-substrate0.6116
CYP450 3A4 substrateSubstrate0.6738
CYP450 1A2 substrateInhibitor0.6812
CYP450 2C9 inhibitorInhibitor0.5672
CYP450 2D6 inhibitorNon-inhibitor0.6789
CYP450 2C19 inhibitorNon-inhibitor0.6475
CYP450 3A4 inhibitorInhibitor0.7906
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8634
Ames testNon AMES toxic0.8205
CarcinogenicityNon-carcinogens0.9164
BiodegradationNot ready biodegradable0.9421
Rat acute toxicity2.5733 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6798
hERG inhibition (predictor II)Inhibitor0.7085
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-MSNot Available
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

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Gene Name
PDE4A
Uniprot ID
P27815
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4A
Molecular Weight
98142.155 Da
References
  1. Muravyov AV, Yakusevich VV, Chuchkanov FA, Maimistova AA, Bulaeva SV, Zaitsev LG: Hemorheological efficiency of drugs, targeting on intracellular phosphodiesterase activity: in vitro study. Clin Hemorheol Microcirc. 2007;36(4):327-34. [Article]
  2. Romics I, Molnar DL, Timberg G, Mrklic B, Jelakovic B, Koszegi G, Blasko G: The effect of drotaverine hydrochloride in acute colicky pain caused by renal and ureteric stones. BJU Int. 2003 Jul;92(1):92-6. [Article]
  3. Pareek A, Chandurkar NB, Patil RT, Agrawal SN, Uday RB, Tambe SG: Efficacy and safety of aceclofenac and drotaverine fixed-dose combination in the treatment of primary dysmenorrhoea: a double-blind, double-dummy, randomized comparative study with aceclofenac. Eur J Obstet Gynecol Reprod Biol. 2010 Sep;152(1):86-90. doi: 10.1016/j.ejogrb.2010.05.007. Epub 2010 Jun 15. [Article]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
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...

Components:
References
  1. Tomoskozi Z, Finance O, Aranyi P: Drotaverine interacts with the L-type Ca(2+) channel in pregnant rat uterine membranes. Eur J Pharmacol. 2002 Aug 2;449(1-2):55-60. [Article]
  2. Romics I, Molnar DL, Timberg G, Mrklic B, Jelakovic B, Koszegi G, Blasko G: The effect of drotaverine hydrochloride in acute colicky pain caused by renal and ureteric stones. BJU Int. 2003 Jul;92(1):92-6. [Article]
  3. Patai Z, Guttman A, Mikus EG: Potential L-Type Voltage-Operated Calcium Channel Blocking Effect of Drotaverine on Functional Models. J Pharmacol Exp Ther. 2016 Dec;359(3):442-451. doi: 10.1124/jpet.116.237271. Epub 2016 Oct 13. [Article]

Drug created at September 07, 2010 21:21 / Updated at April 03, 2021 10:01