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Metoclopramide; Indications, Uses, Dosage, Side Effects, Interactions ,Pregnancy

Metoclopramide is a substituted benzamide and a derivative of para-aminobenzoic acid (PABA) that is structurally related to procainamide, with gastroprokinetic and antiemetic effects. Metoclopramide exerts its prokinetic effect by antagonizing dopamine-mediated relaxation effect on gastrointestinal smooth muscle. This enhances the response of the gastrointestinal smooth muscle to cholinergic stimulation, thereby leading to an increase of gastric emptying into the intestines. Metoclopramide may also strengthen the lower esophagus sphincter, thereby preventing acid reflux. This agent antagonizes D2 dopamine receptors in the chemoreceptive trigger zone (CTZ) of the medulla, thereby preventing nausea and vomiting.

Mechanism of Action of Metoclopramide

Metoclopramide inhibits gastric smooth muscle relaxation produced by dopamine, therefore increasing the cholinergic response of the gastrointestinal smooth muscle. It accelerates intestinal transit and gastric emptying by preventing relaxation of the gastric body and increasing the phasic activity of tantrum. Simultaneously, this action is accompanied by relaxation of the upper small intestine, resulting in an improved coordination between the body and antrum of the stomach and the upper small intestine. Metoclopramide also decreases reflux into the esophagus by increasing the resting pressure of the lower esophageal sphincter and improves acid clearance from the esophagus by increasing amplitude of esophageal peristaltic contractions. Metoclopramide’s dopamine antagonist action raises the threshold of activity in the chemoreceptor trigger zone and decreases the input from afferent visceral nerves. Studies have also shown that high doses of metoclopramide can antagonize 5-hydroxytryptamine (5-HT) receptors in the peripheral nervous system in animals.

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

Metoclopramide is a potent central dopamine-receptor antagonist. The drug has antiemetic and sedative activity. The precise mechanism of antiemetic action of metoclopramide is unclear, but the drug has been shown to directly affect the medullary chemoreceptor trigger zone (CTZ) in the area postrema, apparently by blocking dopamine (e.g., D2) receptors in the CTZ. Metoclopramide increases the CTZ threshold and decreases the sensitivity of visceral nerves that transmit afferent impulses from the GI tract to the vomiting center in the lateral reticular formation. The drug also enhances gastric emptying, which is believed to minimize stasis that precedes vomiting. It also has been suggested that inhibition of serotonin (i.e., 5-HT3) receptors, at least when relatively high doses of metoclopramide are used, may contribute to the antiemetic action of the drug. Metoclopramide inhibits the central and peripheral emetic effects of apomorphine, hydergine, and levodopa.

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Indications of Metoclopramide

Nausea/Vomiting – Chemotherapy Induced
Nausea/Vomiting – Postoperative
Small Intestine Intubation
Gastroesophageal Reflux Disease
Diabetic Gastroparesis
Gastroparesis
Hiccups
Migraines
Prophylaxis against postoperative nausea and vomiting
Reflux, Gastroesophageal
Gastric bezoar
Prophylaxis of acute chemotherapy-induced nausea and vomiting
Prophylaxis of radiation therapy-induced nausea and vomiting
For the treatment of gastroesophageal reflux disease (GERD). It is also used in treating nausea and vomiting, and to increase gastric emptying.

Therapeutic Indications of Metoclopramide

The authorized indications for products are different but can broadly be grouped in the following way

Migraines
Chemotherapy or radiotherapy-induced nausea and vomiting (CINV or RINV)
Post-operative nausea and vomiting (PONV)
Nausea and vomiting associated with a migraine
Nausea and vomiting of other origins
Gastrointestinal motility disorders including gastroparesis
Gastroesophageal reflux disease (GORD) and dyspepsia
Adjuvant to surgical and radiological procedures

Therapeutic Uses of Metoclopramide

Metoclopramide tablets are indicated as short-term (4 to 12 weeks) therapy for adults with symptomatic, documented gastroesophageal reflux who fail to respond to conventional therapy.
Metoclopramide tablets, USP is indicated for the relief of symptoms associated with acute and recurrent diabetic gastric stasis. The usual manifestations of delayed gastric emptying (eg, nausea, vomiting, heartburn, persistent fullness after meals, and anorexia) appear to respond to Metoclopramide Tablets within different time intervals. Significant relief of nausea occurs early and continues to improve over a three-week period. Relief of vomiting and anorexia may precede the relief of abdominal fullness by one week or more.
Metoclopramide injection is indicated for the prophylaxis of vomiting associated with emetogenic cancer chemotherapy.
Metoclopramide injection is indicated for the prophylaxis of postoperative nausea and vomiting in those circumstances where nasogastric suction is undesirable.
Metoclopramide injection may be used to facilitate small bowel intubation in adults and pediatric patients in whom the tube does not pass the pylorus with conventional maneuvers.
Metoclopramide injection may be used to stimulate gastric emptying and intestinal transit of bariumin cases where delayed emptying interferes with radiological examination of the stomach and/or small intestine.
Diamond-Blackfan anemia (DBA) is a congenital anemia characterized by a low reticulocyte count, the absence or severe reduction of hemoglobin-containing cells in the bone marrow, and normal megakaryocytic and granulocytic differentiation. Although the anemia may initially respond to corticosteroid therapy, many patients require lifelong red blood cell (RBC) transfusion, leading to infectious complications and iron overload.

Dosage

Strengths: 10 mg; 5 mg; 5 mg/5 mL; 5 mg/mL; 10 mg/mL

Gastroesophageal Reflux Disease

Symptomatic gastroesophageal reflux disease (GERD): 10 to 15 mg orally up to 4 times a day (30 minutes before meals and at bedtime), depending upon symptoms being treated and clinical response
Intermittent symptoms/at specific times of day: 20 mg orally once a day prior to provoking the situation
Use with esophageal erosions/ulcerations: 15 mg orally 4 times a day, if tolerated
Maximum dose: 60 mg/day
Maximum duration of therapy: 12 weeks

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Nausea/Vomiting – Chemotherapy Induced

Parenteral

Initial dose: 1 to 2 mg/kg/dose (depending on the emetogenic potential of the agent) IV infused over a period of not less than 15 minutes, 30 minutes before administration of chemotherapy.
Subsequent doses: The dose should be repeated every 2 hours for 2 doses following the initial dose, then every 3 hours for 3 additional doses.
Parenteral: 10 to 20 mg IM at or near the end of surgery

Nausea/Vomiting – Postoperative

Parenteral

Initial dose: 1 to 2 mg/kg/dose (depending on the emetogenic potential of the agent) IV infused over a period of not less than 15 minutes, 30 minutes before administration of chemotherapy.
Subsequent doses: The dose should be repeated every 2 hours for 2 doses following the initial dose, then every 3 hours for 3 additional doses.

Small Intestine Intubation

If the tube has not passed the pylorus with conventional maneuvers in 10 minutes, a single undiluted dose may be administered via slow IV.
Parenteral: 10 mg IV metoclopramide base over a 1- to 2-minute period

Gastroparesis

Parenteral: 10 mg IV (slowly over a 1 to 2-minute period) or IM
Maximum duration of therapy: Up to 10 days
Oral: 10 mg orally 30 minutes before each meal and at bedtime for 2 to 8 weeks, depending upon response and the likelihood of continued well-being upon drug discontinuation
Maximum dose: 40 mg/day
Maximum duration of therapy: 12 weeks

Side Effects of Metoclopramide

The most common

Diarrhea
muscle twitching
weakness
Any signs of infection, or a skin rash.
Stomach pain, especially if it comes along with fever and diarrhea or constipation
Yellowing of the skin or eyes
Loss of appetite
Constipation
Chest pain or discomfort
lightheadedness, dizziness, or fainting
unusual tiredness or weakness
the decrease in the amount of urine
fast, pounding, or irregular heartbeat or pulse
false sense of well-being
increased watering of mouth
lightheadedness
constipation;
vision changes;
breast swelling (in men or women); or
decreased sex drive, impotence, or difficulty having an orgasm.
blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
restless muscle movements in your eyes, tongue, jaw, or neck;

Common

Rare

agitation
anxiety
behavioural changes, including aggressiveness, angry outbursts,
confusion
increased trouble sleeping
muscle spasms
shortness of breath
difficult or labored breathing
difficulty with swallowing
dizziness, faintness, or lightheadedness
frequent urination
hallucinations
bloating or swelling of the face, arms, hands, lower legs, or feet
blurred vision
hives or welts, itching, or skin rash
an increased volume of pale, dilute urine

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Drug Interactions of Metoclopramide

Metoclopramide may interact with the following drugs, supplyments, & may change the efficacy of drugs

anticholinergic medications (e.g, tolterodine)
antipsychotics (e.g., chlorpromazine, clozapine, haloperidol, olanzepine, quetiapine,risperidone)
“azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
cyclosporine
levodopa
macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
monoamine oxidase inhibitors (MAOIs; e.g., phenelzine, rasagiline, selegiline,
quinolone antibiotics (e.g., ciprofloxacin, moxifloxacin, levofloxacin)
selective serotonin reuptake inhibitors (SSRI; e.g., fluoxetine, paroxetine, sertraline)
sotalol
tricyclic antidepressants (e.g., amitriptyline, imipramine, nortriptyline)
trimethoprim
tyrosine kinase inhibitors (e.g., nilotinib, sunitinib)
“triptan” migraine medications (e.g., eletriptan, sumatriptan)
tramadol

Pregnancy Category Metoclopramide

Pregnancy

This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

This medication passes into breast milk. If you are a breast-feeding mother and are taking metoclopramide, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding. Metoclopramide should not be used in children less than one year of age. It should only be used in children over one year of age when the benefits of treatment outweigh the risks of side effects. The total daily dose for children should not be higher than 0.5 mg per kilogram of body weight since with higher doses of tremors and abnormal twitching movements can occur.