Metoclopramide
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| Non-proprietary name | Metoclopramide | |||||||||||||||||||||
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4-Amino-5-chloro- N - [2- (diethylamino) ethyl] -2-methoxybenzamide ( IUPAC ) |
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| Molecular formula | C 14 H 22 ClN 3 O 2 | |||||||||||||||||||||
| Brief description |
white to almost white, fine polymorphic powder |
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| Molar mass | 299.80 g · mol -1 | |||||||||||||||||||||
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| pK s value |
9.27 (25 ° C) |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | ||||||||||||||||||||||
Metoclopramide ( MCP ) is a drug from the group of anti-emetics . It stimulates the peristalsis in the upper gastrointestinal tract and thus relieves nausea and vomiting. The effect on postoperative nausea has not been established. In addition, it indirectly promotes the absorption of other drugs or active ingredients by accelerating the peristalsis of the stomach and increasing the opening frequency of the pylorus and is therefore mainly used in migraine preparations in combination with a pain reliever (e.g. ASA , paracetamol ) used. It is on the WHO Essential Medicines List .
Pharmacological properties
Mechanism of action (pharmacodynamics)
MCP is a dopamine antagonist (type D 2 ). Dopamine , as the body's own messenger substance , has an emetic effect, i. H. it can induce vomiting. Dopamine antagonists can also bind to the dopamine receptors and thus block them for dopamine and agonistic substances. A distinction is made between central and peripheral dopamine receptors. Peripheral antagonists can not cross the blood-brain barrier and consequently have little or no effect on the central nervous system, in contrast to central antagonists, which are used as psychotropic drugs . MCP crosses the blood-brain barrier to a certain extent and therefore possibly leads to neuroleptic side effects in the central nervous system .
MCP also influences serotonin receptors : it has a (partial) antagonistic effect on 5-HT 3 , but agonistically on 5-HT 4 receptors, which influence the peristalsis of the gastrointestinal tract and the intestinal secretion of water and electrolytes promote.
Therapeutic use
Due to possible central side effects, MCP requires a prescription in Germany.
application areas
Human medicine
Metoclopramide is indicated for the prevention of nausea and vomiting after chemotherapy and radiation therapy (oral, rectal) and after surgery (parenteral); also for the symptomatic treatment of nausea and vomiting (triggered by migraines, for example) and in the treatment of migraines in combination with oral pain relievers to improve their absorption. After a risk assessment procedure initiated by the European Medicines Agency in 2011 due to the occurrence of adverse, severe neurological and rare but serious cardiovascular effects, the EU Commission decided in December 2013 to restrict the indication, duration of therapy and concentration of metoclopramide in solution or drop form. The maximum duration of the prescription should only be 5 days, while both the recommended single dose remains 10 mg and the recommended daily dose is also unchanged at up to 30 mg for adults. Infants should no longer receive the drug at all. Areas of application such as digestive disorders ( dyspepsia , gastrointestinal motility disorders) and reflux esophagitis , for which there was insufficient evidence of clinically relevant efficacy , should be excluded . According to Bernd Mühlbauer from the Drugs Commission of the German Medical Association (AkdÄ), the doctors have too often prescribed MCP as a panacea. Furthermore, metoclopramide should no longer be used in acute vomiting after chemotherapy, as its effectiveness in the recommended dosage is not considered sufficient, but only in the case of delayed chemotherapy-induced nausea and vomiting.
The Embryonic Toxicology Pharmacovigilance and Consultation Center recommends metoclopramide as the drug of choice for treating nausea and vomiting during pregnancy .
Veterinary medicine
In veterinary medicine, metoclopramide is approved for the symptomatic treatment of vomiting, reduced gastrointestinal motility in inflammation of the gastric mucosa ( gastritis ), gastric cramps ( pyloric spasm ), chronic kidney inflammation ( nephritis ) and digestive intolerance to some veterinary drugs in dogs and cats.
Side effects
Very often there is a feeling of sleepiness. Common side effects include depression , uncontrollable movement disorders such as muscle cramps or tremors, restlessness, dizziness, diarrhea, and a decrease in blood pressure. Occasionally, hallucinations , allergies , impaired consciousness , menstrual disorders or an increased level of prolactin , which can cause milky secretions from the mammary gland in men and women who are not breastfeeding, can occur. Seizures (especially in epileptic patients) or states of confusion are rare .
MCP is possibly the most common trigger for drug-induced movement disorders. There is an increased risk in young patients, high dose and long-term use. Due to possible tardive dyskinesias , the US drug approval authority required manufacturers to post a black box warning . The occurrence of severe neurological and cardiovascular adverse effects prompted a risk assessment process initiated by the European Medicines Agency in December 2011 . In Germany, MCP has been in human medicinal products (monopreparations) in liquid form for oral use with a concentration of more than 1 mg / ml, as a formulation for parenteral use with a concentration of more than 5 mg / ml and for rectal use since April 9, 2014 Use of more than 20 mg no longer marketable due to a withdrawal of authorization. The BfArM is thus implementing the recommendations for minimizing the risk of MCP-containing drugs that the European Medicines Agency (EMA) made on the basis of a reassessment of the risk-benefit ratio. According to the EMA, the risk of serious adverse neurological events can be minimized by using lower doses of metoclopramide.
Another relevant side effect of metoclopramide is an increase in the prolactin level , which can lead to decreased libido, menstrual disorders and impotence .
Contraindications and restrictions on use
Metoclopramide is contraindicated in malaria patients on Malarone therapy or patients taking Malarone prophylaxis . Parkinson's disease is a neurodegenerative disease . Over time, the dopaminergic neurons in the substantia nigra die . The lack of dopamine then leads to the symptoms of this disease, which is also known as "paralysis". Metoclopramide is a dopamine antagonist with the ability to cross the blood-brain barrier and must therefore not be used in Parkinson's disease. Alternatively, domperidone can be used for nausea . In contrast to metoclopramide, domperidone hardly crosses the blood-brain barrier.
Lactation
The pharmaceutical companies advise against the use of metoclopramide and breastfeeding at the same time , since metoclopramide is excreted in breast milk and the effects of dopamine antagonists on the child's nervous system have not been adequately researched. Studies by the Charité's Pharmacovigilance and Advisory Center for Embryonic Toxicology have shown that MCP is only released in small amounts in breast milk and can only cause gas and other side effects in the child in isolated cases. The center recommends using MCP for a short period of time as appropriate. As a dopamine antagonist, MCP is sometimes also used to stimulate the production of breast milk.
chemistry
From a chemical point of view, MCP is 4-amino-5-chloro-N- (2-diethylaminoethyl) -2-methoxybenzamide (also methoxychloroprocainamide ). It is a procainamide derivative, so it belongs to the benzamides , but has no local anesthetic , but a dopamine-antagonistic effect.
synthesis
As a substance class, metoclopramide can be assigned to the aromatic amino acid amides . Thus, the whole range of peptide syntheses is available. To form the amide bond, either the carboxylic acid can be activated, using protective groups of the amino group , or the aliphatic amine is activated.
- Activation of aminobenzoic acid : MCP was developed in 1964 alongside several benzamides at the Delagrange company, now the Sanofi Group, and a patent was applied for as a separate product. Starting from 4-aminosalicylic acid , this is esterified , the amino group acetylated, alkylated with dimethyl sulfate , the aromatic chlorinated and the ester subjected to aminolysis with diethylaminoethylamine. The conversion of the relatively inert ester is catalyzed by aluminum triisopropoxide . The protective group is finally split off with hydrochloric acid ( see reaction scheme ). The mixed anhydride method for MCP was protected relatively late.
- Activation of diethylaminoethylamine : It has long been known that amides can be prepared by acidolysis of phosphorous acid amides. This process is also used for the synthesis of MCP, in which case 4-amino-5-chloro-2-methoxybenzoic acid can also be used directly without using a protective group technique. However, the product is discolored yellow. Phosphazenes are obtained with phosphorus oxychloride , which can also be converted into MCP as a base. The synthesis of MCP by direct acylation of silazanes is also possible without a protective group . This method delivers particularly good conversions if a molar ratio of amine to silicon tetrachloride of 2 to 1 is selected. The preceding application also shows a way in which the use of toxic dimethyl sulfate to form the ether can be circumvented. The copper (I) -catalyzed solvolysis of 2-chlorobenzoic acid derivatives in methanol in the presence of a ligand leads to the corresponding 2-methoxybenzoic acids ( see reaction scheme ).
Polymorphism
Metoclopramide can be isolated as the free base, anhydrous monohydrochloride, dihydrochloride, dihydrochloride hydrate and hydrochloride hydrate. For solid pharmaceutical preparations, the polymorphic form of the active ingredient is of decisive importance for the release rate. Form I of the anhydrous metoclopramide hydrochloride has a melting point of 187 ° C, while the metastable form II already melts at 155 ° C. In the differential thermal analysis (DSC) diagram of form I, two maxima at 97 ° C. and 190 ° C. can be seen at a heating rate of 2 ° C. per minute, resulting from water loss and the melting process. MCP-Base also shows the phenomenon of polymorphism .
Commercial forms and names
Metoclopramide can be administered orally , intravenously, or rectally . The free base is mainly used in suppositories, while the hydrochloride monohydrate ( "Metoclopramide hydrochloride (Ph. Eur.)" ) Is used in tablets, drops and injection solution . In Germany, oral solutions were only available as finished medicinal products in concentrations of 4 to 5 mg / ml. After these were no longer marketable with effect from April 9, 2014, pharmaceutical companies applied for new approvals for correspondingly low-dose preparations. These have been available in a dosage of 1 mg / ml since August 2015.
Ceolat (A), Cerucal (D), Gastronerton (D), Gastrosil (A), Metogastron (A), Paspertin (D, A, CH), Primperan (CH), Geffer (ITA), numerous generics (D)
Migpriv (CH), Migraeflux (D), Migraine-Neuridal (D), Migraenerton (D), Migralave (D)
Emeprid, Vomend
Individual evidence
- ↑ a b European Pharmacopoeia Commission (Ed.): European Pharmacopoeia 5th Edition . tape 5.0-5.8 , 2006.
- ↑ a b c d e The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals , 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006, ISBN 978-0-911910-00 -1 ; Pp. 1058-1059.
- ↑ a b c Entry on metoclopramide in the ChemIDplus database of the United States National Library of Medicine (NLM) .
- ↑ a b Data sheet Metoclopramide hydrochloride from Sigma-Aldrich , accessed on April 10, 2011 ( PDF ).
- ^ J. Wallenborn, L. Eberhart, Peter Kranke: Postoperative nausea and vomiting - everything the same in the pharmacotherapy of PONV? In: anesthesiology, intensive care medicine, emergency medicine, pain therapy. Volume 44, 2009, pp. 296-305; PMID 19367534 .
- ↑ a b c d MCP-ratiopharm ® 1 mg / ml oral solution - ratiopharm GmbH. Retrieved January 14, 2018 .
- ↑ a b European Medicines Agency recommends changes to the use of metoclopramide , EMA press release of July 26, 2013.
- ↑ APOTHEKE ADHOC: “Doctors should have been more stringent” .
- ↑ a b Embryotox.de: Drug safety in pregnancy and lactation: Database drugs and active ingredients: Metoclopramid ( Memento from September 9, 2013 in the Internet Archive ).
- ↑ Specialist information Emeprid, as of May 2010.
- ↑ Instructions for use MCP-AbZ 1mg / ml solution. AbZ-Pharma, accessed October 19, 2019 .
- ^ US Food and Drug Administration: FDA Requires Boxed Warning and Risk Mitigation Strategy for Metoclopramide-Containing Drugs . In: Press Announcements . US Food and Drug Administration. February 26, 2009. Retrieved July 16, 2011.
- ↑ BfArM: Metoclopramide-containing drugs: Implementation of the implementation decision of the EU Commission , April 23, 2014.
- ↑ Pharmaceutical newspaper online: BfArM calls MCP back , April 16, 2014.
- ↑ Red List
- ↑ Patent BE648164 : Nouveux procédé de preparation de benzamides substités .. Published on November 20, 1964 , inventor: Leon Thominet Michel (Ile de France).
- ↑ Patent DE1518271 : Process for the production of substituted benzamides .. Published on December 17, 1970 , inventor: Leon Thominet Michel (Societe d'Etudes Scientifiques et Industrielles de l'Ile-de-France).
- ↑ Patent DE2327192 : Process for the preparation of 2-alkoxy-4,5-disubstituted benzamides. Published on December 13, 1973 , inventor: Bulteau Gerard, Acher Jaques (Societe d'Etudes Scientifiques et Industrielles de l'Ile-de-France ).
- ↑ Goldschmidt Stefan, Krauss, HL: N-substituted amides of phosphorus and phosphoric acid and their use to build peptide bonds. In: Angew. Chem. Band 57 , no. 17-18 , 1955, pp. 471-475 , doi : 10.1002 / anie.19550671705 .
- ↑ Patent DE1932512 : Process for the production of therapeutically active N diethyl-aminoethyl-2-methoxy-4-amino-5-chlorobenzamide and its physiologically active salts. Published on October 19, 1972 , inventor: Murakami Masuo, Inukai Norioshi, Koda Akio . Nakano Koji (YAMANOUCHI PHARMA CO LTD).
- ↑ Patent DE1966453 : New process for the preparation of N- (diethylaminoethyl) 4-amino-2-methoxybenzamides. Published on January 8, 1970 , inventor: Meri Broms (HUHTAMAEKI YHTYMAE OY LAEAEKET).
- ↑ Patent DE2162947 : New process for the production of benzamide derivatives. Published on September 7, 1972 , inventors: Nakajima I., Tsuijkawa K., Kato Yukuru, Shinuchi Tadami (TEIKOKU CHEMICAL IND.).
- ↑ Patent DE2342934 : Process for the production of Benzamidverbindungen. Published on March 28, 1974 , inventor: Podesva, Ctirad; Scott, William Thomas; Navratil, Milada M .; Kishner, Lynda D .; (Delmar Chemicals Ltd.).
- ↑ Patent DE2365988 : Process for the production of N-dialkylaminoethyl-2-alkoxy-4-aminobenzoic acid amides .. Published on March 17, 1977 , inventor: Liebenow Walter, Grafe Ingomar (LUDWIG HEUMANN & Co GmbH).
- ↑ Patent DE2335439 : Process for the production of N-dialkylaminoethyl-2-alkoxy-4-amino-benzoic acids .. Published on February 6, 1975 , inventor: Request for non-naming (LUDWIG HEUMANN & Co GmbH).
- ^ Maria Esther Dias Reis, Jennifer Tavares Jacon, Mônica Esselin, de Sousa Lino, Juliana Savioli Simões et al .: Polymorphism: an evaluation of the potential risk to the quality of drug products from the Farmácia Popular Rede Própria . In: Brazilian Journal of Pharmaceutical Sciences . tape 50 , 2014, p. 1 , doi : 10.1590 / S1984-82502011000100002 (English).
- ^ A b AG Mitchell: Polymorphism in metoclopramide hydrochloride and metoclopramide . In: Journal of Pharmacy and Pharmacology . tape 37 , no. 9 , 1985, pp. 601–604 , doi : 10.1111 / j.2042-7158.1985.tb05093.x (English).
- ↑ APOTHEKE ADHOC: MCP recall tears a loophole , April 16, 2014.
- ↑ MCP drops are back ( Memento from December 9, 2015 in the Internet Archive ), July 30, 2015.
See also
Web links
- Entry on metoclopramide at Vetpharm, accessed on August 5, 2012.
