Metoclopramide: A Review of its Pharmacological Properties and Clinical Use
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Synopsis: 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 those with jaundice. It significantly increases the rate of gastric emptying and reduces the transit time for barium to reach the caecum. Controlled trials have shown that small intestine examinations are complete within 1 hour in over 80% of metoclopramide-treated patients compared with in less than 20% of untreated patients. Both oral and intravenous metoclopramide were superior to placebo in speeding gastric emptying and reducing the number of films needed for complete visualisation of the small intestine, but in one study oral metoclopramide gave an increased number of radiographically poor examinations.
Metoclopramide is useful in facilitating duodenal intubation ad permitting rapid and successful biopsy of the small intestine, in the absence of significant side-effects. It speeds the passage of biopsy capsules across the pylorus, and was significantly superior to both placebo and pharyngeal anaesthesia in controlled trials. In patients with functional pyloric stenosis, metoclopramide facilitated endoscopic observation of the duodenal bulb.
Emergency endoscopy of upper gastro-intestinal haemorrhage is facilitated by the administration of metoclopramide, which clears the viewing area of blood. However, it is possible that the increased stomach activity may in itself cause further haemorrhage.
Side-effects with metoclopramide are usually mild, transient, and readily reversed by withdrawal of drug. A review of one published trial suggests that they occur in about 11% of patients, but the incidence may be different in clinical practice. They consist principally of drowsiness and lassitude, bowel disturbances, and dizziness and faintness. Metoclopramide may increase lactation by stimulating the release of prolactin.
Extrapyramidal effects are alarming but uncommon (in about 1% of patients). They consist of dystonic reactions such as trismus, torticollis, facial spasms, opisthotonos, and oculogyric crises, but Parkinsonian-like symptoms are absent. Metoclopramide-induced dystonia occurs more often in females and in the young patient; when it occurs it is usually following excessive doses, but may also occur at normal therapeutic dosage, and resembles in many respects the dyskinesias induced by the phenothiazines. It responds readily to withdrawal of drug, but severe cases may benefit from intramuscular benztropin or diazepam. Children are particularly susceptible, but restriction of the daily dose to 0.5mg/kg usually prevents overdosage in young patients. Signs of overdosage in children usually include extreme irritability and agitation, with muscle hypertonia. Two adult cases of attempted suicide with 360 and 800mg metoclopramide recovered uneventfully following gastric lavage and observation; somnolence and disorientation were reported, but there were no extrapyramidal signs.
Contra-indications and precautions: Metoclopramide should neither be given with, or within 2 weeks of treatment with monoamine oxidase inhibitors, tricyclic antidepressants, or sympathomimetic drugs, nor to women in the first 3 months of pregnancy, as the safety of use of such associations has not been established. It may potentiate the central action of some antipyschotic drugs, and its own action on the gastro-intestinal tract may be potentiated by acetylcholine-like drugs and blocked by atropine-like agents. It should not be given with phenothiazines.
The ability of metoclopramide to provide symptomatic relief in gastro-intestinal disorders does not replace proper investigation and diagnosis of the patient’s symptoms. Metoclopramide should not be given to patients with epilepsy or extrapyramidal syndromes, though it may be safely used in Parkinsonian patients to control vomiting. The dosage for children should be carefully adjusted from initially low levels. Increasing the adult dosage beyond the recommended level does not normally lead to a corresponding enhancement of therapeutic effects.
Dosage: Metoclopramide is given before or just after meals, or 20 minutes before symptoms are likely to occur, in oral, intramuscular, or intravenous doses of 10mg, up to 3 times daily, in adults, and 5 to 10mg 2 to 3 times daily in young adults. Children under 14 should receive 1 to 5mg, 2 to 3 times daily, according to age and body weight. The total daily dose in children and young adults should not exceed 0.5mg/kg.
For diagnostic purposes, the adult dose is 20mg orally, 20 minutes before examination, or 10 to 20mg by injection 5 minutes before examination. Children receive, according to age and body weight, 1 to 5mg, 5 to 10 minutes before examination.
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