Domperidon

Introduction to Domperidone

Domperidone is a dopamine-2 receptor antagonist primarily used as an antiemetic and prokinetic agent. It acts on the gastrointestinal tract to enhance gastric motility and alleviate nausea and vomiting. Unlike metoclopramide, domperidone does not penetrate the blood-brain barrier significantly, which minimizes neurological side effects and enhances its safety profile for long-term use . This article explores the diverse applications of domperidone in clinical settings, supported by comprehensive data tables and case studies.

Gastrointestinal Disorders

Gastroparesis and Nonulcer Dyspepsia

Domperidone has been effectively utilized in managing gastroparesis, a condition characterized by delayed gastric emptying. A study involving patients with idiopathic gastric stasis demonstrated that while motility was unchanged, symptom scores significantly improved in those treated with domperidone compared to placebo . This highlights its role in symptomatic relief rather than direct motility enhancement.

Gastroesophageal Reflux Disease (GERD)

Recent research indicates that combining domperidone with proton pump inhibitors (PPIs) may provide superior outcomes in GERD management. A systematic review showed that this combination significantly reduced reflux episodes and improved symptom scores compared to PPIs alone . The efficacy of domperidone in this context is further illustrated in the following table:

Lactation Support

Domperidone is frequently prescribed off-label to stimulate milk production in breastfeeding women. A case study documented a nursing mother who successfully increased her milk supply using domperidone, although she experienced withdrawal symptoms upon discontinuation after prolonged use . This application underscores the compound's utility beyond gastrointestinal disorders.

Neurological Applications

While primarily indicated for gastrointestinal issues, domperidone has been investigated for its potential benefits in treating certain neurological conditions associated with nausea and vomiting, such as migraines. Its efficacy in these contexts remains an area of ongoing research.

Safety Profile and Side Effects

Domperidone is generally well-tolerated, with a favorable safety profile due to its limited central nervous system penetration. Common side effects include gastrointestinal disturbances such as abdominal cramps or diarrhea. However, serious adverse effects are rare when used at recommended doses .

Case Studies on Safety

A notable case involved a breastfeeding woman who experienced withdrawal symptoms after abrupt cessation of domperidone following eight months of use. Symptoms included tachycardia and anxiety, indicating that prolonged exposure may lead to tolerance and subsequent withdrawal challenges .

Target of Action

Domperidone is a dopamine receptor antagonist . It primarily targets dopamine receptors, specifically the D2 receptors . These receptors play a crucial role in the regulation of gastrointestinal motility and the chemoreceptor trigger zone, which is involved in the control of nausea and vomiting .

Mode of Action

Domperidone interacts with its targets by blocking dopamine receptors . This blockade results in two main actions: a central action on the chemoreceptor trigger zone and a peripheral action on gastrointestinal motility . By blocking dopamine receptors, domperidone enhances gastrointestinal peristalsis and lowers the incidence of nausea and vomiting .

Biochemical Pathways

Domperidone affects the dopaminergic pathways. Stimulation of dopaminergic receptors typically inhibits gastric motility. By antagonizing these receptors, domperidone enhances gastric motility and speeds up gastrointestinal peristalsis . This results in improved gastric emptying and reduced symptoms such as post-prandial bloating and pain, premature satiety, nausea, and vomiting .

Pharmacokinetics

Upon oral administration, domperidone is rapidly absorbed, with peak plasma levels achieved within 30 to 60 minutes . It demonstrates a high plasma protein binding rate of up to 93% . Domperidone is metabolized in the liver and gut wall during the first-pass effect . The systemic bioavailability after oral administration is 13 to 17% , while it is about 90% after intramuscular administration .

Result of Action

The molecular and cellular effects of domperidone’s action include enhanced gastrointestinal peristalsis and reduced incidence of nausea and vomiting . In addition, domperidone has been found to inhibit cell proliferation via targeting MEK and CDK4 in esophageal squamous cell carcinoma .

Biochemical Properties

Domperidone works by blocking the peripheral dopamine receptor, which results in its gastroprokinetic action . It increases gastric peristalsis and antroduodenal coordination to facilitate gastric emptying . The anti-emetic properties of Domperidone are due to its dopamine (D2) receptor-blocking activity at the chemoreceptor trigger zone (CTZ) .

Cellular Effects

Domperidone influences cell function by affecting the motor function of the stomach and small intestine, as well as the chemoreceptor trigger zone . It does not have any negative neurological effects like sedation and dystonia due to its very little penetration through the blood-brain barrier .

Molecular Mechanism

Domperidone exerts its effects at the molecular level by blocking dopamine receptors . This blockade speeds gastrointestinal peristalsis and causes prolactin release .

Temporal Effects in Laboratory Settings

Domperidone has a very good safety profile for long-term oral administration in the prescribed doses . The drug induces cardiac arrest when given intravenously .

Dosage Effects in Animal Models

The effects of Domperidone vary with different dosages in animal models

Metabolic Pathways

Domperidone is involved in dopamine receptor pathways . It interacts with dopamine receptors and blocks them, which leads to its antiemetic and prokinetic effects .

Transport and Distribution

Domperidone is a lipophilic drug with a low oral bioavailability and a high rate of first-pass metabolism . To improve its bioavailability when administered orally, its water solubility must be increased and first-pass metabolism must be overcome .

Subcellular Localization

It is known that Domperidone has very little penetration through the blood-brain barrier, which prevents it from causing negative neurological effects .

Domperidon kann durch die Kupplungsreaktion zweier Benzimidazolonderivate synthetisiert werden. Die Synthesewege umfassen die Cyclisierung von o-Phenylendiamin mit Carbonylreagenzien, gefolgt von der Kupplung mit 1,3-Dihalogenpropan. Ein weiterer Weg umfasst die Kupplungsreaktion von o-Halogen- oder o-Aminonitrobenzol mit 1,3-disubstituiertem Propan, gefolgt von Reduktion und Cyclisierung. Der letztere Weg vermeidet die Bildung von disubstituierten Nebenprodukten und weist eine höhere Reaktionsselektivität auf .

Industrielle Produktionsverfahren für this compound-Tabletten umfassen die direkte Pulverkompression des Rohmaterials. Der Prozess umfasst das Vermahlen des Rohmaterials, das Mischen mit Hilfsstoffen wie Carboxymethylstärke-Natrium, vorgegelatinierter Stärke, mikrokristalliner Cellulose und Magnesiumstearat und anschliessend die Tablettierung des Gemisches .

Chemische Reaktionsanalyse

This compound unterliegt verschiedenen chemischen Reaktionen, darunter:

Oxidation: this compound kann unter bestimmten Bedingungen oxidiert werden, was zur Bildung von oxidierten Derivaten führt.

Reduktion: Reduktionsreaktionen können Nitrogruppen in Aminogruppen umwandeln, die für die Synthese von this compound-Zwischenprodukten essentiell sind.

Substitution: Substitutionsreaktionen, wie z. B. Halogenierung, können die chemische Struktur von this compound verändern und zu verschiedenen Derivaten führen.

Häufige Reagenzien, die in diesen Reaktionen verwendet werden, sind Carbonylreagenzien, 1,3-Dihalogenpropan und Reduktionsmittel. Die Hauptprodukte, die aus diesen Reaktionen gebildet werden, sind Benzimidazolonderivate und substituierte Nitrobbenzolderivate .

Domperidone undergoes various chemical reactions, including:

Oxidation: Domperidone can be oxidized under specific conditions, leading to the formation of oxidized derivatives.

Reduction: Reduction reactions can convert nitro groups to amino groups, which are essential in the synthesis of domperidone intermediates.

Substitution: Substitution reactions, such as halogenation, can modify the chemical structure of domperidone, leading to different derivatives.

Common reagents used in these reactions include carbonyl reagents, 1,3-dihalopropane, and reducing agents. The major products formed from these reactions are benzimidazolone derivatives and substituted nitrobenzene derivatives .

Domperidon wird oft mit anderen Dopaminrezeptor-Antagonisten wie Metoclopramid verglichen. Im Gegensatz zu Metoclopramid hat this compound eine geringere Tendenz, die Blut-Hirn-Schranke zu überwinden, was zu weniger Nebenwirkungen auf das zentrale Nervensystem führt. Dies macht this compound zur bevorzugten Wahl für Patienten, die gegenüber neurologischen Nebenwirkungen empfindlich sind .

Ähnliche Verbindungen sind:

Metoclopramid: Ein weiterer Dopaminrezeptor-Antagonist, der für ähnliche Indikationen eingesetzt wird, aber ein höheres Risiko für Nebenwirkungen auf das zentrale Nervensystem aufweist.

Cisaprid: Ein Prokinetikum, das ebenfalls die Magen-Darm-Motilität verbessert, aber mit schweren kardialen Nebenwirkungen in Verbindung gebracht wurde.

Itoprid: Ein Dopamin-D2-Rezeptor-Antagonist und Acetylcholinesterase-Inhibitor, der bei Magen-Darm-Erkrankungen eingesetzt wird.

Die einzigartige Fähigkeit von this compound, periphere Dopaminrezeptoren selektiv zu blockieren und gleichzeitig Nebenwirkungen auf das zentrale Nervensystem zu minimieren, unterscheidet es von anderen ähnlichen Verbindungen .

Domperidone is an antiemetic agent primarily used to treat nausea and vomiting. It acts as a peripheral dopamine D2 receptor antagonist, which influences gastrointestinal motility and has been explored for various therapeutic applications beyond its conventional uses. This article delves into the biological activity of domperidone, summarizing its mechanisms, pharmacological effects, and recent research findings.

Domperidone selectively blocks dopamine D2 and D3 receptors located in the gastrointestinal tract and the chemoreceptor trigger zone (CTZ) in the brain. By inhibiting these receptors, domperidone increases gastric motility and accelerates gastric emptying, which helps alleviate symptoms of nausea and vomiting. Additionally, it stimulates prolactin release from the pituitary gland, which may have immunomodulatory effects .

Pharmacological Effects

The pharmacological effects of domperidone can be summarized as follows:

• Antiemetic Activity : Reduces nausea and vomiting.
• Gastrointestinal Motility : Enhances gastric emptying and intestinal transit.
• Prolactin Stimulation : Increases prolactin levels, potentially influencing immune responses.

Recent Research Findings

• Antiviral Activity Against SARS-CoV-2 :
  A recent clinical trial investigated the efficacy of domperidone in reducing viral load in patients with mild-to-moderate COVID-19. The study found that while domperidone exhibited in vitro antiviral activity against SARS-CoV-2, it did not significantly reduce viral load compared to placebo in clinical settings. Adverse events were reported in both groups, with no hospitalizations occurring .
• Antitumor Activity in Breast Cancer :
  Research has shown that domperidone exhibits cytotoxic effects on triple-negative breast cancer (TNBC) cell lines (BT-549 and CAL-51). The study concluded that domperidone could be a potential therapeutic agent for TNBC due to its ability to induce apoptosis in cancer cells .
• Effects on Orthostatic Hypotension :
  Domperidone has been evaluated for its effectiveness in managing orthostatic hypotension, particularly in Parkinson's disease patients. It was noted to help improve symptoms associated with this condition, although further studies are needed to establish its safety profile .

Case Study 1: Domperidone for COVID-19

A double-blind clinical trial conducted in Spain involved 173 outpatients with mild-to-moderate COVID-19 who received either 30 mg/day of domperidone or a placebo for seven days. The primary endpoint was the reduction of viral load measured by RT-qPCR. While there was a statistically significant reduction in viral load at day 4 compared to baseline, the difference between treatment and placebo groups was not significant at later time points .

Case Study 2: Domperidone in Breast Cancer

In vitro studies on TNBC cells demonstrated that treatment with domperidone resulted in significant cytotoxicity. The mechanism was linked to the induction of apoptosis via modulation of signaling pathways associated with cell survival and death .

Summary of Biological Activities