Metoclopramide

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Abstract
Synopsis: Since previously reviewed in the Journal (Vol. 12, No. 2), metoclopramide has been confirmed as an effective drug in treating and preventing various types of vomiting and as a useful agent in oesophageal reflux disease, gastroparesis, dyspepsia, and in a variety of functional gastrointestinal disorders. Of considerable importance is the recent evidence of its efficacy when administered intravenously in high dosages in preventing severe vomiting associated with cisplatin. Good results have been achieved in patients not previously treated with cisplatin, but further studies are needed to determine its level of efficacy in patients who have experienced severe vomiting during earlier courses of cytotoxic therapy. Side effects consisting of mild sedation, diarrhoea and reversible extrapyramidal reactions have occurred, but are tolerated by many patients. Pharmacodynamic Studies: Pharmacodynamic studies in man have shown that oral and intravenous metoclopramide rapidly influences gastrointestinal tract motility. The effect of the drug in increasing lower oesophageal sphincter pressure is more marked in volunteers than patients with reflux oesophagitis or pregnant patients, and appears to be directly related to basal pressure, dose and route of administration. Gastric emptying studies employing radioisotope-labelled liquid and solid meals have demonstrated increased emptying in patients with delayed gastric emptying associated with diabetes, vagotomy and other gastric surgery. The effect of metoclopramide on gastric contractions is most pronounced in the antrum. Metoclopramide stimulates contraction of intestinal smooth muscle, resulting in a decreased transit time through the small intestine, but any effect on colonic activity remains to be clarified. Metoclopramide is effective in preventing apomorphine-induced vomiting in man, and in animals prevents vomiting induced by apomorphine, hydergine, reserpine, tetrodotoxin and copper sulphate, by raising the threshold for vomiting at the chemoreceptor trigger zone as well as by peripheral mechanisms. Other effects on the gastrointestinal tract are thought to result from inhibition of dopaminergic receptors, potentiation of cholinergic effects and/or a direct action on smooth muscle. The neuroleptic-like central nervous system effects of metoclopramide probably result from blockade of cerebral dopamine receptors by the parent drug rather than by a metabolite. Oral or intravenous metoclopramide stimulates prolactin release in all recipients. Pharmacokinetics: Peak plasma metoclopramide concentrations occur within 1 hour of oral administration. On average, concentrations 1 hour after 20 and 40mg doses are about 40 and 80 ng/ml, respectively, but may show interindividual variation because of ‘first-pass’ hepatic metabolism. In crossover studies, relative bioavailability was lower after rectal administration of 40mg than after an oral dose of 26.7mg. The mean volume of distribution is about 2 to 3 L/kg. Metoclopramide readily enters breast milk where drug concentrations exceed those in plasma 2 hours after oral administration. 80% of an oral dose is excreted in the urine within 24 hours, either as unchanged drug (20%) or sulphate and glucuronide conjugates of metoclopramide. Elimination half-life has been reported as 2.6 to 5 hours in healthy subjects and around 14 hours in patients with moderate to severe renal impairment. Therapeutic Trials: Controlled trials have shown oral metoclopramide 30 to 40mg daily to alleviate the symptoms of gastro-oesophageal reflux relative to placebo and in some studies to also increase lower oesophageal sphincter pressure. However, as with many other drugs used in oesophageal reflux disease, endoscopic healing of oesophagitis has still to be adequately demonstrated with metoclopramide. Some patients with gastroparesis associated with diabetes mellitus or vagotomy have benefited from treatment with metoclopramide 40mg daily. However, there are no established criteria to predict which patients may benefit most and gastric emptying rates are not a reliable indication of response. Metoclopramide has been successfully used to treat dyspepsia, being more effective than placebo, the anticholinergic drug pipenzolate and the antiemetic agent prochlorperazine. Similarly, metoclopramide appears to be useful in a variety of functional gastrointestinal disorders including irritable bowel syndrome, spastic constipation, and functional diarrhoea but studies in these conditions and in dyspepsia have generally been poorly designed. There is no firm evidence that the drug promotes the healing of peptic ulcer. Results of studies in the prevention of postoperative vomiting have been variable, with metoclopramide proving effective and comparable with the peripheral dopamine antagonist domperidone when administered intravenously immediately prior to general anaesthesia. As with other drugs used in prevention of postoperative vomiting, response to metoclopramide has been influenced by the interval between administration and induction of anaesthesia, the anaesthetic drugs, postoperative use of narcotic analgesics and variation in surgical procedures. Recent well conducted studies have shown high dose intravenous metoclopramide (1 to 2 mg/kg for 5 or 6 doses) to be effective in preventing the severe vomiting caused by cisplatin therapy (50 to 120 mg/m2). Best results to date have been achieved in patients not previously exposed to antineoplastic drugs, and in patients previously treated with cisplatin whose initial vomiting had been well controlled. In patients receiving cisplatin for the first time, high dose metoclopramide was superior to placebo, intramuscular prochlorperazine and oral tetrahydrocannabinol. Metoclopramide has been used to control vomiting associated with narcotic analgesics, radiation therapy, pregnancy, gastroenteritis, gastric carcinoma, hepatic and biliary disorders, chronic renal failure, cardiac disease and alcoholism. The delayed absorption caused by poor gastric emptying associated with migraine attacks appears to be corrected by metoclopramide, resulting in earlier attainment of therapeutic plasma concentrations of concomitantly administered analgesics, but this has yet to be confirmed in appropriately designed controlled trials. The drug has been widely used as an adjunct in radiological examination of the small bowel to facilitate the passage of barium, and is useful in facilitating intubation and in speeding the passage of biopsy capsules across the pylorus. Side Effects: At usual therapeutic doses metoclopramide is well tolerated. Side effects are generally mild and transient and seldom necessitate withdrawal of the drug. They consist principally of drowsiness, restlessness, bowel disturbances, dizziness and faintness after oral or parenteral administration. At usual doses, extrapyramidal effects are infrequent in adults, but occur more often at the higher dosages used to prevent vomiting caused by antineoplastic drugs and in patients with renal failure. These reactions respond to reduction of dose, withdrawal of the drug, or treatment with intramuscular benztropine, diphenhy-dramine or diazepam. A dose-related increase in drowsiness is evident with high intravenous doses used to treat cisplatin-induced vomiting. Further experience is needed to determine the incidence of side effects with high and intermediate doses of intravenous metoclopramide, particularly in children and young adults. Dosage: The usual oral intramuscular or intravenous dose in adults is 10mg 3 or 4 times daily before meals or before symptoms are likely to occur. Children under 14 years should receive 0.1 mg/kg per dose, the total daily dose not to exceed 0.5 mg/kg/day. For diagnostic purposes, the adult dose is 20mg orally 20 minutes before examination or 10 to 20mg parenterally 5 minutes before examination. For the prevention of cisplatin-induced vomiting in adults, metoclopramide should be iluted in 50ml of an intravenous solution and infused over a period of at least 15 minutes. At present it is recommended that administration should begin 30 minutes before cisplatin and be repeated 2-hourly for 2 doses and 3-hourly for 3 doses. The initial doses should be 2 mg/kg, and if vomiting is controlled, subsequent doses may be decreased to 1 mg/g. However, the optimum dosage recommendations, particularly in children and young adults, remain to be established.