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
Structure for Drotaverine (DB06751)
- 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
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- Abdominal Pain caused by Gall Stones
- Abdominal Pain caused by Kidney Stones
- Muscle Spasms
- Spastic Pain
- Spastic Pain caused by Cystitis
- Spastic Pain caused by Funicular Nephritis
- Spastic Pain caused by Gallbladder disorders
- Spastic Pain caused by Physical Examination
- Spastic Pain caused by cholecysitis
- Spastic Pain of the Gastrointestinal Tract
- Contraindications & Blackbox Warnings
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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
Target Actions Organism AcAMP-specific 3',5'-cyclic phosphodiesterase 4A inhibitorHumans UVoltage-dependent L-type calcium channel inhibitorHumans - 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
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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.
Drug Interaction Integrate drug-drug
interactions in your softwareIsosorbide mononitrate Drotaverine may increase the vasodilatory activities of Isosorbide mononitrate. Patent Blue The therapeutic efficacy of Drotaverine can be decreased when used in combination with Patent Blue. Riociguat Drotaverine may increase the hypotensive activities of Riociguat. 
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- No interactions found.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Drotaverine hydrochloride 24ZVH4C669 985-12-6 JBFLYOLJRKJYNV-MASIZSFYSA-N - International/Other Brands
- Drotin / No-Spa (Sanofi-Aventis) / Taverin
Categories
- ATC Codes
- A03AD02 — Drotaverine
- Drug Categories
- Alimentary Tract and Metabolism
- Alkaloids
- Analgesics
- Autonomic Agents
- Benzylisoquinolines
- Cardiovascular Agents
- Central Nervous System Agents
- Drugs for Functional Gastrointestinal Disorders
- Heterocyclic Compounds, Fused-Ring
- Isoquinolines
- Opiate Alkaloids
- Papaverine and Derivatives
- Parasympatholytics
- Peripheral Nervous System Agents
- Phosphodiesterase 4 Inhibitors
- Phosphodiesterase Inhibitors
- Sensory System Agents
- Vasodilating Agents
- 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
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- Magyar K, Lengyel M, Knoll J: Absorption, distribution and elimination of drotaverine. Acta Physiol Acad Sci Hung. 1978;51(4):401-11. [Article]
- Cayman Chemical: Drotaverine Safety Data Sheet [Link]
- FDA Thailand: Spablock (Drotaverine) Oral Tablet [Link]
- External Links
- Human Metabolome Database
- HMDB0015669
- PubChem Compound
- 1712095
- PubChem Substance
- 99443287
- ChemSpider
- 1361582
- BindingDB
- 50237620
- 23684
- ChEBI
- 135630
- ChEMBL
- CHEMBL551978
- ZINC
- ZINC000100011979
- PharmGKB
- PA165958398
- Wikipedia
- Drotaverine
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Terminated Treatment Menstrual Distress (Dysmenorrhea) 1 3 Completed Prevention Bile Duct Diseases / ERCP / Pancreatic Diseases 1 2 Unknown Status Diagnostic Effect of Meperidine or Drotaverine on Effacement and Dilatation of the Cervix During Labor in Full Term Primigravidae 1 2, 3 Completed Treatment Failure of Cervical Dilation as Antepartum Condition / Mild Birth Asphyxia, APGAR 4-7 / Pain, Labor / Prolonged First Stage of Labor 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution 20 mg/1ml Tablet Oral Tablet Oral 40 mg Tablet, coated Oral 40 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 197 https://datasheets.scbt.com/sds/aghs/en/sc-211384.pdf - Predicted Properties
Property Value Source Water Solubility 0.002 mg/mL ALOGPS logP 5.35 ALOGPS logP 4.19 ChemAxon logS -5.3 ALOGPS pKa (Strongest Basic) 7.4 ChemAxon Physiological Charge 1 ChemAxon Hydrogen Acceptor Count 5 ChemAxon Hydrogen Donor Count 1 ChemAxon Polar Surface Area 48.95 Å2 ChemAxon Rotatable Bond Count 9 ChemAxon Refractivity 117.99 m3·mol-1 ChemAxon Polarizability 46.99 Å3 ChemAxon Number of Rings 3 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule No ChemAxon MDDR-like Rule Yes ChemAxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9958 Blood Brain Barrier + 0.753 Caco-2 permeable + 0.6023 P-glycoprotein substrate Substrate 0.8447 P-glycoprotein inhibitor I Inhibitor 0.7972 P-glycoprotein inhibitor II Non-inhibitor 0.8544 Renal organic cation transporter Non-inhibitor 0.625 CYP450 2C9 substrate Non-substrate 0.7958 CYP450 2D6 substrate Non-substrate 0.6116 CYP450 3A4 substrate Substrate 0.6738 CYP450 1A2 substrate Inhibitor 0.6812 CYP450 2C9 inhibitor Inhibitor 0.5672 CYP450 2D6 inhibitor Non-inhibitor 0.6789 CYP450 2C19 inhibitor Non-inhibitor 0.6475 CYP450 3A4 inhibitor Inhibitor 0.7906 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.8634 Ames test Non AMES toxic 0.8205 Carcinogenicity Non-carcinogens 0.9164 Biodegradation Not ready biodegradable 0.9421 Rat acute toxicity 2.5733 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.6798 hERG inhibition (predictor II) Inhibitor 0.7085
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Targets
- 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
- 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]
- 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]
- 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
- 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]
- 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]
- 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