MELASIL TABLETS

Indications

• Nausea and vomiting associated with chemotherapy
• Postoperative nausea and vomiting
• Gastroparesis
• Gastroesophageal reflux disease (GERD)
• Dyspepsia

Dosage

Children: For children

Adults: The usual adult dose for nausea and vomiting is 10 mg taken 30 minutes before meals and at bedtime, up to 3 times a day. The maximum duration of treatment should not exceed 12 weeks.

Mechanism of action

Metoclopramide exerts its antiemetic effects by inhibiting dopamine D2 and serotonin 5-HT3 receptors in the chemoreceptor trigger zone (CTZ) of the brain. It promotes prokinetic effects through actions on presynaptic and postsynaptic D2 receptors, agonizing serotonin 5-HT4 receptors, and antagonizing muscarinic receptors. This leads to enhanced release of acetylcholine, increasing lower esophageal sphincter (LES) and gastric tone, accelerating gastric emptying and intestinal transit.

Pharmacodynamics

Metoclopramide increases gastric emptying by decreasing LES pressure and prevents nausea and vomiting through its effects on the area postrema of the brain. It enhances gastrointestinal motility without increasing biliary, gastric, or pancreatic secretions. However, due to its antidopaminergic activity, prolonged use can lead to adverse effects such as tardive dyskinesia, dystonia, and akathisia, necessitating a treatment duration limit of 12 weeks.

Pharmacokinetics

Metoclopramide is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1-2 hours after oral administration. It is metabolized primarily in the liver, and its elimination half-life ranges from 5 to 6 hours. The drug is excreted mainly via the kidneys, with about 80% of a dose eliminated in the urine as metabolites. Dose adjustments may be necessary in patients with renal impairment.

Contra-indications

• Known hypersensitivity to metoclopramide
• Pheochromocytoma
• Gastrointestinal obstruction, perforation, or hemorrhage
• Severe renal impairment
• History of tardive dyskinesia or other extrapyramidal symptoms from previous treatment with antidopaminergic agents

Adverse effects

• Drowsiness
• Fatigue
• Diarrhea
• Dystonia
• Akathisia
• Tardive dyskinesia
• Restlessness
• Headache
• Dry mouth
• Nausea

Interactions

• May enhance the sedative effects of CNS depressants
• Anticholinergic agents may counteract the effects of metoclopramide
• Drugs that increase gastrointestinal motility may have additive effects
• Concomitant use with other antidopaminergic agents can increase the risk of extrapyramidal symptoms

Precautions

• Use with caution in patients with epilepsy
• Monitor for signs of extrapyramidal symptoms
• Consider dosage adjustment in patients with renal impairment
• Should not be used for longer than 12 weeks due to the risk of tardive dyskinesia
• Pregnant and breastfeeding women should use with caution

Pregnancy

Metoclopramide should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Metoclopramide is excreted in breast milk; caution is advised when administering to nursing mothers.

Storage

Store in a well-closed container at room temperature, away from moisture and light.

Formulations

• Tablets
• Oral solution
• Intravenous injection
• Intramuscular injection

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.

Pharmacodynamics

Metoclopramide increases gastric emptying by decreasing lower esophageal sphincter (LES) pressure. It also exerts effects on the area postrema of the brain, preventing and relieving the symptoms of nausea and vomiting. In addition, this drug increases gastrointestinal motility without increasing biliary, gastric, or pancreatic secretions. Because of its antidopaminergic activity, metoclopramide can cause symptoms of tardive dyskinesia (TD), dystonia, and akathisia, and should therefore not be administered for longer than 12 weeks.