Wikipedia

Itopride

Itopride(INN;brand nameGanaton) is aprokineticbenzamidederivative. These drugs inhibitdopamineand acetylcholine esterase enzyme and have agastrokineticeffect.[3]Itopride is indicated for the treatment offunctional dyspepsiaand other gastrointestinal conditions.[4]It is a combinedD2receptorantagonistandacetylcholinesterase inhibitor.[5][6]Itoprideis the dimethoxy analog oftrimethobenzamide.

Itopride
Clinical data
Trade namesGanaton
AHFS/Drugs.comInternational Drug Names
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokineticdata
Bioavailability~60% (Tmax= 35±5 min)
Protein binding96%
MetabolismExtensive hepatic (FMO1andFMO3), primarilyN-oxidation[2]
Eliminationhalf-life5.7±0.3 hours
ExcretionRenal(3.7–4.1% as unchanged itopride, 75.4–89.4% as itopride-N-oxide)[1]
Identifiers
  • N-[[4-(2-Dimethylaminoethoxy)phenyl]methyl]-3,4-dimethoxybenzamide
CAS Number
PubChemCID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.222.888Edit this at Wikidata
Chemical and physical data
FormulaC20H26N2O4
Molar mass358.438g·mol−1
3D model (JSmol)
  • CN(C)CCOC1=CC=C(C=C1)CNC(=O)C2=CC(=C(C=C2)OC)OC

  • as HCl: Cl.COC1=CC=C(C=C1OC)C(=O)NCC1=CC=C(OCCN(C)C)C=C1
  • InChI=1S/C20H26N2O4/c1-22(2)11-12-26-17-8-5-15(6-9-17)14-21-20(23)16-7-10-18(24-3)19(13-16)25-4/h5-10,13H,11-12,14H2,1-4H3,(H,21,23)☒N
  • Key:QQQIECGTIMUVDS-UHFFFAOYSA-N☒N

  • as HCl: InChI=1S/C20H26N2O4.ClH/c1-22(2)11-12-26-17-8-5-15(6-9-17)14-21-20(23)16-7-10-18(24-3)19(13-16)25-4;/h5-10,13H,11-12,14H2,1-4H3,(H,21,23);1H
  • Key:ZTOUXLLIPWWHSR-UHFFFAOYSA-N-UHFFFAOYSA-N
☒NcheckY(what is this?)(verify)

Medical uses

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A blister package of Ganaton (Itopride) 50 mg tablets intended for distribution in theSlovak Republic.

Typically, itopride is indicated in the treatment of GI symptoms caused by reduced GI motility:

Itopride was shown to significantly improve symptoms in patients with functional dyspepsia and motility disorders in placebo-controlled trials.

These studies concluded that the reduction in the severity of symptoms offunctional dyspepsiaafter 8 weeks of treatment with itopride indicated that itopride was significantly superior to placebo and that itopride yielded a greater rate of response than placebo in significantly reducing pain and fullness.[11]

Adverse drug reactions

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Central nervous system adverse effects do not tend to occur due to poor penetration across the blood brain barrier, although a slight raising of prolactin levels may occur.[7]Raising of prolactin levels is more common with high dose regimes of itopride.[12]

Cardiac studies

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Itopride belongs to the samebenzamidegroup ascisapride,a drug found to affectQT intervaland possibly predispose those using it to cardiacarrhythmias.However, itopride does not have any adverse effect on the QT interval.[7]

Later, in a study conducted with healthy adult volunteers, itopride was shown as unlikely to cause cardiac arrhythmias or ECG changes in part to the lack of significant interaction and metabolism via thecytochrome P450enzyme pathway, unlikecisaprideandmosapride,as it is metabolized by a different enzyme set. New molecular studies on guinea pig ventricularmyocytesalso supported the cardiac safety profile of itopride, as it did not affect certain potassium mechanisms that may have been affected by cisapride or mosapride. Moreover, itopride has no affinity for the5-HT4receptors, unlike otherbenzamidessuch as cisapride and mosapride, which are 5-HT4agonists. The affinity of cisapride for 5-HT4receptors in the heart has been implicated in the undesirable cardiac effects of cisapride itself.[medical citation needed]

The conclusion of this study revealed that itopride is devoid of any abnormal effect onQT interval.Therefore, it may be possible that itopride could be considered as a better and certainly safer prokinetic agent than eithercisaprideormosapride,and itopride should also be considered a welcome treatment addition for symptomatic nonulcer dyspepsia and other gastric motility disorders.[13]

Pharmacology

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Itopride acts as a selective dualD2receptorantagonistandacetylcholinesterase inhibitor.[5][6]

There is evidence that itopride may have prokinetic effects throughout the gastrointestinal tract from the stomach to the end of the colon.[14]The pharmacokinetics of itopride appear to differ between Asian and Caucasian populations, with Caucasians having 30-50 percent lower blood levels of itopride after oral administration.[15]Itopride poorly penetrates across the blood brain barrier because of its high polarity and thus itopride does not tend to cause anycentral nervous systemadverse effects.[7]Itopride has no effect onpotassium channels.[16]

Similarly to other D2receptor antagonists, itopride has been found to dose-dependently increaseprolactinlevels.[6]

Pharmacokinetics

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After oral administration itopride undergoes rapid and extensive absorption with levels of itopride peaking in the blood plasma after only 35 minutes. Itopride is primarily eliminated via the kidneys having anelimination half-lifeof approximately 6 hours.[17]

Mechanism of action

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Ganaton (Itopride) 50 mg tablets. Engraving says "HC 803"

Itopride increasesacetylcholineconcentrations by inhibitingdopamine D2 receptorsandacetylcholinesterase.Higher acetylcholine increases GIperistalsis,increases the lower esophageal sphincter pressure, stimulates gastric motility, accelerates gastric emptying, and improves gastro-duodenal coordination.[7]

Itopride given as a single dose study found that it also raises levels ofmotilin,somatostatinand lowers levels ofcholecystokinin,as well asadrenocorticotropic hormone.These effects may also contribute to itopride's pharmacology.[18]

Society and culture

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Names

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Itopride is available under various brand names including Ganaton (Japan, Czech Republic, Russian Federation), Itoprid PMCS (Czech Republic, Slovakia), Itomed (Kyrgyzstan, Kazakhstan, Moldova, Russia, Ukraine, Uzbekistan), Prokit (Poland), and Itogard (Nepal). In Mexico, itopride is sold by Takeda Laboratories under the brand name Dagla. In Bulgaria and other countries of East Europe itopride is sold by Zentiva under the brand name Zirid[19]

References

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  1. ^"Ganaton (itopride hydrochloride) Tablets 50 mg. Prescribing Information"(PDF).Abbott Japan Co., Ltd. Archived fromthe original(PDF)on 11 December 2015.Retrieved9 December2015.
  2. ^Smith DA, Allerton C, Kubinyi H, van de Waterbeemd H, Walker DK, eds. (April 2012).Pharmacokinetics and Metabolism in Drug Design(3rd ed.). Weinheim: Wiley-VCH. p. 132.ISBN978-3-527-32954-0.
  3. ^Iwanaga Y, Miyashita N, Saito T, Morikawa K, Itoh Z (June 1996)."Gastroprokinetic effect of a new benzamide derivative itopride and its action mechanisms in conscious dogs".Japanese Journal of Pharmacology.71(2): 129–137.doi:10.1254/jjp.71.129.PMID8835639.
  4. ^Holtmann G, Talley NJ, Liebregts T, Adam B, Parow C (February 2006)."A placebo-controlled trial of itopride in functional dyspepsia".The New England Journal of Medicine.354(8): 832–840.doi:10.1056/NEJMoa052639.PMID16495395.
  5. ^abParkman HP, McCallum RW (5 October 2011).Gastroparesis: Pathophysiology, Presentation and Treatment.Springer. pp. 264–.ISBN978-1-60761-552-1.
  6. ^abcChey WY, Chey WD (2011).Irritable Bowel Syndrome, an Issue of Gastroenterology Clinics.Elsevier Health Sciences. pp. 232–.ISBN978-1-4557-0450-7.
  7. ^abcdeHuang X, Lv B, Zhang S, Fan YH, Meng LN (December 2012)."Itopride therapy for functional dyspepsia: a meta-analysis".World Journal of Gastroenterology.18(48): 7371–7377.doi:10.3748/wjg.v18.i48.7371.PMC3544044.PMID23326147.
  8. ^Chiba T, Tokunaga Y, Ikeda K, Takagi R, Chishima R, Terui T, et al. (September 2007). "Effects of itopride hydrochloride and ranitidine in patients with functional dyspepsia: comparison between prokinetic and acid suppression therapies".Hepato-Gastroenterology.54(78): 1878–1881.PMID18019739.{{cite journal}}:CS1 maint: overridden setting (link)
  9. ^Keil R (May 2004). "[Prokinetics and diabetes mellitus]".Vnitrni Lekarstvi.50(5): 358, 360–358, 362.PMID15305632.
  10. ^Kojecky V, Bernatek J, Bakala J, Weissova D (2005). "[The influence of itopride on the rate and course of the evacuation of stomach of the diabetic patients and their relationship to diabetes control]".Ces.Slov.Gastroent.Hepatol., 2005.59(1): 17–20.
  11. ^Holtmann G, Talley NJ, Liebregts T, Adam B, Parow C (February 2006)."A placebo-controlled trial of itopride in functional dyspepsia".The New England Journal of Medicine.354(8): 832–840.doi:10.1056/NEJMoa052639.PMID16495395.
  12. ^Kim YS, Kim TH, Choi CS, Shon YW, Kim SW, Seo GS, et al. (July 2005)."Effect of itopride, a new prokinetic, in patients with mild GERD: a pilot study".World Journal of Gastroenterology.11(27): 4210–4214.doi:10.3748/wjg.v11.i27.4210.PMC4615444.PMID16015691.{{cite journal}}:CS1 maint: overridden setting (link)
  13. ^Gupta S, Kapoor V, Gupta BM, Verma U (2005)."Effect Of Itopride hydrochloride on QT interval in adult healthy volunteers"(PDF).JK-Practitioner.12(4): 207–10.
  14. ^Lim HC, Kim YG, Lim JH, Kim HS, Park H (June 2008)."Effect of itopride hydrochloride on the ileal and colonic motility in guinea pig in vitro".Yonsei Medical Journal.49(3): 472–478.doi:10.3349/ymj.2008.49.3.472.PMC2615341.PMID18581598.
  15. ^Stevens JE, Russo A, Maddox AF, Rayner CK, Phillips L, Talley NJ, et al. (May 2008). "Effect of itopride on gastric emptying in longstanding diabetes mellitus".Neurogastroenterology and Motility.20(5): 456–463.doi:10.1111/j.1365-2982.2007.01058.x.PMID18179609.S2CID25760696.{{cite journal}}:CS1 maint: overridden setting (link)
  16. ^Morisawa T, Hasegawa J, Hama R, Kitano M, Kishimoto Y, Kawasaki H (1999). "Effects of itopride hydrochloride on the delayed rectifier K+ and L-type CA2+ currents in guinea-pig ventricular myocytes".Research Communications in Molecular Pathology and Pharmacology.106(1–2): 37–45.PMID11127807.
  17. ^Bose A, Wong TW, Singh N (April 2013)."Formulation development and optimization of sustained release matrix tablet of Itopride HCl by response surface methodology and its evaluation of release kinetics".Saudi Pharmaceutical Journal.21(2): 201–213.doi:10.1016/j.jsps.2012.03.006.PMC3744972.PMID23960836.
  18. ^Katagiri F, Shiga T, Inoue S, Sato Y, Itoh H, Takeyama M (2006). "Effects of itopride hydrochloride on plasma gut-regulatory peptide and stress-related hormone levels in healthy human subjects".Pharmacology.77(3): 115–121.doi:10.1159/000093485.PMID16717477.S2CID22219251.
  19. ^"Z".
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