Metoclopramida
Descripción general
Descripción
Metoclopramida es un medicamento que se usa principalmente para tratar las náuseas y los vómitos, así como para facilitar el vaciado gástrico en pacientes con vaciado estomacal retardado. También se usa para controlar la enfermedad por reflujo gastroesofágico y las cefaleas migrañosas .
Mecanismo De Acción
La metoclopramida ejerce sus efectos principalmente antagonizando los receptores de dopamina D2 en el sistema nervioso central. Esta acción interfiere con los mecanismos centrales que crean la sensación de náuseas y estimula la contracción del esfínter esofágico inferior y la motilidad gástrica . Además, la this compound actúa como antagonista del receptor 5-HT3 y como agonista del receptor 5-HT4, lo que contribuye aún más a sus efectos procinéticos .
Aplicaciones Científicas De Investigación
La metoclopramida tiene una amplia gama de aplicaciones de investigación científica, que incluyen:
Química: Se utiliza como compuesto modelo en estudios que involucran agentes procinéticos y antagonistas de los receptores de dopamina.
Biología: Se estudia por sus efectos sobre la motilidad gastrointestinal y sus interacciones con varios receptores.
Medicina: Se utiliza ampliamente en entornos clínicos para tratar náuseas, vómitos y gastroparesia.
Análisis Bioquímico
Biochemical Properties
Metoclopramide interacts with various enzymes and proteins, primarily through its antagonistic effects on dopamine D2 and serotonin 5-HT3 receptors . It also exhibits agonistic effects on serotonin 5-HT4 receptors and antagonizes muscarinic receptor inhibition . These interactions play a crucial role in its function in biochemical reactions .
Cellular Effects
Metoclopramide has significant effects on various types of cells and cellular processes. It influences cell function by inhibiting dopamine D2 and serotonin 5-HT3 receptors in the chemoreceptor trigger zone (CTZ) located in the area postrema of the brain . This leads to prokinetic effects via inhibitory actions on presynaptic and postsynaptic D2 receptors, agonism of serotonin 5-HT4 receptors, and antagonism of muscarinic receptor inhibition .
Molecular Mechanism
Metoclopramide exerts its effects at the molecular level through several mechanisms. It inhibits dopamine D2 and serotonin 5-HT3 receptors in the chemoreceptor trigger zone (CTZ) of the brain . This leads to prokinetic effects via inhibitory actions on presynaptic and postsynaptic D2 receptors, agonism of serotonin 5-HT4 receptors, and antagonism of muscarinic receptor inhibition .
Temporal Effects in Laboratory Settings
The effects of Metoclopramide can change over time in laboratory settings. The risk of acute neurological effects is higher in children than in adults . The review has confirmed a well‐established safety profile for metoclopramide, including the risks of neurological adverse effects (e.g. acute extrapyramidal symptoms and irreversible tardive dyskinesia) .
Dosage Effects in Animal Models
The effects of Metoclopramide can vary with different dosages in animal models. The dosage must be adapted in animals with renal or hepatic insufficiency due to an increase in the risk of side effects . The dosage should be carefully observed, especially in cats and small breed dogs .
Metabolic Pathways
Metoclopramide undergoes first-pass metabolism and its metabolism varies according to the individual . This drug is metabolized by cytochrome P450 enzymes in the liver . CYP2D6 and CYP3A4 both contribute to its metabolism, with CYP2D6 being more heavily involved .
Transport and Distribution
The volume of distribution of Metoclopramide is approximately 3.5 L/kg . This implies a high level of tissue distribution. Metoclopramide crosses the placental barrier and can cause extrapyramidal symptoms in the fetus .
Subcellular Localization
Given its mechanism of action, it is likely to be found in areas where dopamine D2 and serotonin 5-HT3 receptors are present, such as the chemoreceptor trigger zone (CTZ) located in the area postrema of the brain .
Métodos De Preparación
Rutas de Síntesis y Condiciones de Reacción
La metoclopramida se puede sintetizar mediante varios métodos. Un método común implica la reacción del ácido 4-amino-5-cloro-2-metoxibenzoico con N,N-dietil-2-cloroetilamina en presencia de una base para formar el compuesto intermedio, que luego se convierte en this compound mediante reacciones adicionales .
Métodos de Producción Industrial
La producción industrial de this compound generalmente implica la preparación de clorhidrato de this compound. El proceso incluye la disolución de this compound en una solución de ácido tartárico, seguida de la adición de pirosulfito de sodio y una solución de acetato de sodio para ajustar el pH. Luego, la solución se filtra y se somete a varios pasos de purificación para obtener el producto final .
Análisis De Reacciones Químicas
Tipos de Reacciones
La metoclopramida experimenta varios tipos de reacciones químicas, que incluyen:
Oxidación: La this compound se puede oxidar para formar varios metabolitos.
Reducción: Las reacciones de reducción pueden modificar los grupos funcionales presentes en la this compound.
Sustitución: Las reacciones de sustitución pueden ocurrir en el anillo aromático u otros grupos funcionales.
Reactivos y Condiciones Comunes
Los reactivos comunes utilizados en las reacciones que involucran this compound incluyen agentes oxidantes como el peróxido de hidrógeno, agentes reductores como el borohidruro de sodio y varios ácidos y bases para reacciones de sustitución .
Principales Productos Formados
Los principales productos formados a partir de estas reacciones incluyen varios metabolitos y derivados de this compound, que pueden tener diferentes propiedades farmacológicas .
Comparación Con Compuestos Similares
Compuestos Similares
Algunos compuestos similares a la metoclopramida incluyen:
Domperidona: Otro antagonista del receptor de dopamina que se usa para tratar las náuseas y los vómitos.
Proclorperazina: Se utiliza para controlar las náuseas, los vómitos y las cefaleas migrañosas.
Clorpromazina: Un medicamento antipsicótico con propiedades antieméticas.
Singularidad de la this compound
La this compound es única en su combinación de antagonismo del receptor de dopamina D2 y antagonismo del receptor 5-HT3 / agonismo del receptor 5-HT4, lo que proporciona un amplio espectro de efectos procinéticos y antieméticos. Esto la hace particularmente efectiva en el control de afecciones como la gastroparesia y las náuseas severas .
Propiedades
IUPAC Name |
4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C14H22ClN3O2/c1-4-18(5-2)7-6-17-14(19)10-8-11(15)12(16)9-13(10)20-3/h8-9H,4-7,16H2,1-3H3,(H,17,19) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
TTWJBBZEZQICBI-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CCN(CC)CCNC(=O)C1=CC(=C(C=C1OC)N)Cl |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C14H22ClN3O2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Related CAS |
2576-84-3 (di-hydrochloride), 54143-57-6 (mono-hydrochloride, mono-hydrate), 7232-21-5 (mono-hydrochloride) |
Source
|
| Record name | Metoclopramide [INN:BAN:JAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000364625 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
DSSTOX Substance ID |
DTXSID6045169 |
Source
|
| Record name | Metoclopramide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID6045169 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
299.79 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Metoclopramide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015363 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
Crystal; decomposes at 145 °C. Solubility at 25 °C (g/100 mL): water 48; ethanol (95%) 9; absolute ethanol 6; benzene 0.10; chloroform 0.10. Stable in acidic solutions. Unstable in strongly alkaline solutions. /Metoclopramide Dihydrochloride monohydrate/, Solubility at 25 °C (g/100 mL): 95% ethanol 2.30; absolute ethanol 1.90; benzene 0.10; chloroform 6.60, In water, 0.02 g/100 mL at 25 °C, 3.10e-01 g/L |
Source
|
| Record name | Metoclopramide | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7841 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Metoclopramide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015363 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Mechanism of Action |
Metoclopramide causes antiemetic effects by inhibiting dopamine D2 and serotonin 5-HT3 receptors in the chemoreceptor trigger zone (CTZ) located in the area postrema of the brain. Administration of this drug leads to prokinetic effects via inhibitory actions on presynaptic and postsynaptic D2 receptors, agonism of serotonin 5-HT4 receptors, and antagonism of muscarinic receptor inhibition. This action enhances the release of acetylcholine, causing increased lower esophageal sphincter (LES) and gastric tone, accelerating gastric emptying and transit through the gut. Metoclopramide antagonizes the dopamine D2 receptors. Dopamine exerts relaxant effect on the gastrointestinal tract through binding to muscular D2 receptors., Metoclopramide accelerates gastric emptying and intestinal transit from the duodenum to the ileocecal valve by increasing the amplitude and duration of esophageal contractions, the resting tone of the lower esophageal sphincter, and the amplitude and tone of gastric (especially antral) contractions and by relaxing the pyloric sphincter and the duodenal bulb, while increasing peristalsis of the duodenum and jejunum. Unlike nonspecific cholinergic-like stimulation of upper GI smooth muscle, the stimulant effects of metoclopramide on GI smooth muscle coordinate gastric, pyloric, and duodenal motor activity., The pharmacologic actions of metoclopramide on the upper GI tract are similar to those of cholinergic drugs (e.g., bethanechol); however, unlike cholinergic drugs, metoclopramide does not stimulate gastric, biliary, or pancreatic secretions and does not affect serum gastrin concentration. Although the exact mechanism of action of metoclopramide is unclear, the effects of metoclopramide on GI motility may be mediated via enhancement of cholinergic excitatory processes at the postganglionic neuromuscular junction; antagonism of nonadrenergic, noncholinergic inhibitory motor nerves (i.e., dopaminergic); and/or a direct effect on smooth muscle., The effects of metoclopramide on GI motility do not depend on intact vagal innervations but are reduced or abolished by anticholinergic drugs (e.g., atropine) and potentiated by cholinergic drugs (e.g., carbachol, methacholine). These findings suggest that metoclopramide's effects on GI motility may depend in part on intramural cholinergic neurons of smooth muscle that are intact after vagal denervation. Unlike cholinergic drugs, metoclopramide requires intrinsic neuronal storage sites of acetylcholine to exert its pharmacologic effects. Postsynaptic activity results from metoclopramide's ability to enhance release of acetylcholine from postganglionic cholinergic neurons in the GI tract and to sensitize muscarinic receptors of GI smooth muscle to the actions of acetylcholine., Metoclopramide is a potent dopamine-receptor antagonist, and some of the actions of metoclopramide on GI smooth muscle may be mediated via antagonism of dopaminergic neurotransmission, Specific dopamine receptors in the esophagus and stomach have been identified; however, it is not known if there is a dopaminergic control system for smooth muscle function in the upper GI tract. In the GI tract, dopamine is principally an inhibitory neurotransmitter. Dopamine decreases the intensity of esophageal contractions, relaxes the proximal stomach, and reduces gastric secretion. Although metoclopramide blocks these inhibitory effects of dopamine, the actual role of dopamine in the peripheral control of GI motility has not been fully elucidated. Since cholinergic mechanisms are responsible for most excitatory motor activity in the GI tract, it appears that metoclopramide's therapeutic effects are principally caused by the drug's cholinergic-like activity; however, antagonism of GI dopaminergic activity may augment metoclopramide's cholinergic-like activity., For more Mechanism of Action (Complete) data for Metoclopramide (10 total), please visit the HSDB record page. |
Source
|
| Record name | Metoclopramide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01233 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Metoclopramide | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7841 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
CAS No. |
364-62-5 |
Source
|
| Record name | Metoclopramide | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=364-62-5 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Metoclopramide [INN:BAN:JAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000364625 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Metoclopramide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01233 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Metoclopramide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID6045169 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Metoclopramide | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.006.058 | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | METOCLOPRAMIDE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/L4YEB44I46 | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
| Record name | Metoclopramide | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7841 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Metoclopramide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015363 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Melting Point |
171-173, 146.5-148 °C, 147.25 °C |
Source
|
| Record name | Metoclopramide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01233 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Metoclopramide | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7841 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Metoclopramide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015363 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Synthesis routes and methods
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