R. Pinder, R. N. Brogden, P. Sawyer
2012
Citations
1
Influential Citations
69
Citations
Quality indicators
Journal
Drugs
Abstract
SummarySynopsis: Metoclopramide 1 , 4-amino-5-chlorO’2-methoxy-N-(2-diethyl-aminoethyl) benzamide, is advocated for use in gastro-intestinal diagnostics, and in treating various types of vomiting and a variety of functional and organic gastro-intestinal disorders.Published data have indicated that metoclopramide assists radiological identification of lesions in the small intestine, facilitates duodenal intubation and small intestine biopsy, and eases emergency endoscopy in upper gastro-intestinal haemorrhage. Metoclopramide reduces post-operative vomiting and radiation sickness, and ameliorates some types of drug-induced vomiting. It may provide symptomatic relief in dyspepsia and possibly in vertigo, reflux oesophagitis and hiccups, but further controlled trials are needed to confirm the efficacy of metoclopramide in these proposed areas of use. It promotes gastric emptying prior to anaesthesia. Its effects in healing gastric ulcer and preventing relapse of duodenal ulcer remain unproven.Side-effects are few and transient, though alarming extrapyramidal reactions can occur in a small proportion of patients receiving therapeutic doses but more usually following excessive doses in young subjects. They respond rapidly to withdrawal of the drug. Pharmacodynamic studies in man and in a variety of experimental animals have established that metoclopramide, after oral or intravenous administration, rapidly affects the motility of the gastro-intestinal tract. Its effects include improved resting tone of the oesophageal sphincter, improved tone and peristalsis of the stomach with accelerated gastric emptying (but with slowing in some cases), enhanced pyloric activity, distension of the duodenal bulb, and increased peristalsis of the duodenum with accelerated transit through the duodenum and jejunum. It has comparatively little overall effect on colonic motor activity in vivo. The actions of metoclopramide on motility are blocked by atropine and can be reproduced in vitro on animal and human smooth muscle. It is unclear whether the drug is effective in all post-vagotomy patients. Metoclopramide has no effect on gastric secretion, and may sensitise gut muscle to the action of endogenous acetylcholine.The accelerated gastric emptying usually produced by metoclopramide is reflected in its effects on the absorption of other drugs. Intramuscular metoclopramide promoted the absorption of salicylate from the depressed levels associated with attacks of migraine to those characteristic of normal subjects. Paracetamol absorption was both accelerated and enhanced in normal subjects. Metoclopramide also accelerated absorption of tetracycline and pivampicillin, ethanol, and levodopa, but did not affect that of isoniazid. The absorption of digoxin from slow-release tablets was depressed by multiple doses of metoclopramide given to patients on maintenance digoxin therapy.Metoclopramide is effective in preventing apomorphine-induced vomiting in man, and appears to be equipotent with prochlorperazine but superior to trimethobenzamide. In animals it is a potent antagonist of vomiting induced by apomorphine, hydergine, reserpine, tetrodotoxin and copper sulphate. Metoclopramide has behavioural properties in animals which suggest that it is a central dopaminergic antagonist, and it may exert its anti-emetic effects by blocking the chemoreceptor trigger zone for vomiting. In cats, spontaneous electrical discharges from this part of the central nervous system were abolished by metoclopramide and stimulated by apomorphine. Other effects of metoclopramide on the central nervous system include typical neuroleptic properties in animals; catalepsy and reversal of the behavioural stereotypies produced by apomorphine or amphetamine. In man, however, metoclopramide is without significant antipsychotic or sedative properties.Metoclopramide lacks significant cardiovascular effects, and large intravenous doses in patients with heart disease had no marked influence on haemodynamic parameters. Intracardiac conduction is unaffected by metoclopramide, though large doses prevent experimentally-induced cardiac arrhythmias in animals and produce a slight and transient decrease in blood pressure. Metoclopramide has a negligible effect on blood pressure responses in animals to acetylcholine, adrenaline, histamine and noradrenaline but it blocks the hypotensive action of dopamine. Pharmacokinetic studies of metoclopramide in man are limited, but animal experiments suggest that the drug is well absorbed and rapidly excreted, with a short half-life and only partial metabolism by O-demethylation, N-de-ethylation and amide hydrolysis. Maximum plasma levels occur within 30 to 120 minutes of oral dosage, and human studies indicate that levels of 0.2gmg/ml are achieved following intramuscular doses of 40mg. Plasma half-life in animals is 1 to 2 hours, and metoclopramide is distributed principally to the intestinal mucosa, liver, biliary tract, and salivary glands. Within the central nervous system the drug is localised at the area postrema, which contains the chemoreceptor trigger zone for vomiting. Metoclopramide binds only moderately to human plasma protein and 24% of the dose was excreted unchanged in the first 24 hours following an intramuscular dose of 40mg in human volunteers. Therapeutic trials under controlled conditions have shown that metoclopramide in intramuscular doses of 10 to 20mg is significantly better than placebo in controlling postoperative vomiting. Metoclopramide was also slightly more effective than prochlorperazine (10mg, im) in one study and significantly superior to perphenazine (5mg, im) in one of two studies but there was no significant difference between metoclopramide (20mg, iv) and trimethobenzamide (300mg, iv). The effects of metoclopramide seem to be independent of either the type of anaesthetic or the premedicant used but for optimum effect may need to be given towards the end of the operation. Controlled trials have demonstrated that 10mg intramuscular metoclopramide is significantly superior to placebo, perphenazine (5mg, im), or prochlorperazine (10mg, im) in preventing vomiting due to pethidine or morphine. The drug was effective in women during labour, in the elderly, and in surgical patients, and it abolished pre-operative vomiting associated with pethidine administration. Clinical experience suggests that daily doses of 30 to 80mg metoclopramide are effective in controlling nausea and vomiting in Parkinsonian patients receiving levodopa, without compromising the therapeutic efficacy of levodopa. However, controlled trials show that the drug has no place in relieving emesis induced by some cytostatic drugs or by iodipamide.Radiation sickness was ameliorated by daily metoclopramide, which was not significantly different in its effect from prochlorperazine. Metoclopramide was indistinguishable from prochlorperazine and significantly superior to placebo in a controlled trial in the relief of vomiting of pregnancy, without apparent deleterious effects on the fetus. Clinical experience confirms these effects, but like all new drugs metoclopramide should probably not be given to women during the first 3 months of pregnancy since its safety in use has not been established, despite the lack of dysmorphogenic effects in animals. Limited controlled trials show that metoclopramide may be useful in providing symptomatic relief, particularly from nausea and vomiting, in patients with a variety of disorders. Further controlled trials in large groups of selected patients are needed to confirm these effects.Results of a controlled study indicate that metoclopramide may be effective in treating nausea and vomiting of vertigo and certain associated disorders, but it appears to have no place in the treatment of seasickness. Migraine may respond to the drug, but in the studies to date patients have continued to take their usual analgesic medication, the absorption of which is promoted by metoclopramide. The lack of sufficient controlled trials, however, leaves the role of metoclopramide in these disorders uncertain.Dyspepsia responds to metoclopramide, which was significantly superior to placebo or the anticholinergic drug pipenzolate in controlled trials. Metoclopramide was more effective in controlling nausea, vomiting, epigastric burning, heartburn, and regurgitation of sour fluid than the flatulent symptoms of belching, bloating, and abdominal distension. Nevertheless, there is still some debate as to whether metoclopramide is effective in preventing gastro-oesophageal reflux. Metoclopramide may be useful in treating hiccup.Limited controlled trials suggest that metoclopramide provides symptomatic relief and may accelerate the healing of gastric ulcer and prevent relapse of duodenal ulcer, but its role remains unproven. Some functional gastro-intestinal disorders appear to respond to metoclopramide. In controlled trials, it was significantly more effective than carbachol or placebo in relieving post-vagotomy gastric stasis, superior to placebo in alleviating gastritis and gastroptosis, and as effective as isopropamide plus haloperidol against irritable colon and spastic constipation. It has been used successfully in the conservative management of complete pyloric obstruction due to duodenal ulcer, in order to avoid emergency surgery but it probably should not be used in pyloric stenosis due to carcinoma or severe fibrosis.The dual action of metoclopramide in preventing emesis and accelerating gastric emptying, has established its use in anaesthetic practice. It is especially useful in emergency anaesthesia, including during labour, when rapid clearance of gastric contents is required. Diagnostic uses: In diagnostic radiology or cineradiology, metoclopramide given before barium meal provides excellent conditions for the diagnosis of lesions in the duodenum, jejunum and ileum, and prevents vomiting of barium in nauseated patients such as thos