Use Of Metoclopramide Research Articles

Pharmacokinetics of high-dose metoclopramide in cancer patients.

The introduction of new cytotoxic drug regimens has been associated with an increase in the incidence and severity of adverse effects. This in turn has highlighted the need for more effective adjuvant therapy. The use of metoclopramide for the prophylaxis of nausea and vomiting, in high intravenous doses (50 to 1000 mg), has become established since 1981. As a lipid-soluble drug, metoclopramide has a large volume of distribution. The reported mean values after high doses range between 2.8 and 4.6 L/kg. The mean values for total body clearance and terminal half-life range from 0.31 to 0.69 L/kg/h and from 4.5 to 8.8 hours, respectively. The values of these pharmacokinetic parameters are essentially similar to those obtained after conventional doses (less than 50mg). Pharmacokinetic parameters appear unaffected by age, although no high-dose study has been conducted in children. Bodyweight is apparently correlated with clearance. An influence of renal function indices on terminal half-life and clearance has been shown, which is rather surprising since renal clearance accounts for only 20% of the total clearance. No thorough investigations exist which examine the influence of hepatic disease, cancer type and cytotoxic drug regimen on the disposition of metoclopramide. A relationship between dose (or concentration) and therapeutic or adverse effects of metoclopramide is outlined. The therapeutic benefit of high doses (up to 14 mg/kg) may be dependent on age, and on the combination of cytotoxic drugs. The advantages of high doses of metoclopramide are most apparent when the drug is used as protection against the adverse effects of high doses of cisplatin (greater than 60 mg/m2). Despite considerable pharmacokinetic variability, intravenous administration of high doses of metoclopramide is relatively safe due to its large therapeutic index.

Potential uses for metoclopramide.

Metoclopramide, a dopamine antagonist, is approved in the U.S. for the treatment of various gastrointestinal disorders. Its use has been investigated in a wide variety of diseases, including those not involving the intestinal tract. Although more study is required before routine clinical use of metoclopramide can be advocated, it may be effective in the treatment of tardive dyskinesia, in decreasing the risk factors associated with anesthetic-related aspiration, and as an adjunct in the treatment of gastric bezoars. It also may be used safely in patients with Parkinson's disease. The use of metoclopramide in the treatment of neurogenic bladder, orthostatic hypotension, tumor-associated gastroparesis, nonprolactinemic amenorrhea, failure to thrive, Tourette's syndrome, anorexia nervosa, and hiccups, as well as an adjunct to migraine therapy, has been investigated, but sufficient evidence has not been accumulated to advocate the use of metoclopramide in these disorders.

The use of methylprednisolone and metoclopramide in control of emesis in patients receiving cis-platinum

cis-Platinum is a chemotherapeutic agent with benefits often limited by the severe gastrointestinal reactions it produces in nearly all patients. Persistent anorexia, nausea, and vomiting may continue for days after therapy and are poorly controlled by conventional antiemetics. Patients at times refuse continuation of cis-platinum chemotherapy because of these severe gastrointestinal side effects. Intravenous methylprednisolone (Solu-medrol) as well as intravenous metoclopramide (Reglan) have been shown effective in the treatment of chemotherapy-induced nausea and vomiting. This randomized, double-blind study is a comparison of the efficacy of Solu-medrol vs Reglan, as well as, the combination of Solu-medrol and Reglan in the prevention of cis-platinum-induced nausea and vomiting. In this study patients receiving Reglan had better protection from vomiting than patients receiving Solu-medrol ( P = 0.0564). Patients receiving the combination of Reglan and Solu-medrol had better protection from vomiting than patients receiving Reglan alone ( P = 0.0332), or patients receiving Solu-medrol alone ( P = 0.0010). Finally, older patients experienced less vomiting than younger patients, regardless of the anti-emetic drugs used ( P = 0.0730).

Use of Metoclopramide to Prevent 1080-Induced Emesis in Wild Pigs

Use of Metoclopramide to Prevent 1080-Induced Emesis in Wild Pigs

Effect of metoclopramide on gastric liquid emptying in patients with diabetic gastroparesis.

Metoclopramide tablets have been approved for use in the acute and chronic management of diabetic gastroparesis. Its efficacy as an antiemetic has been well documented. We measured the acute and chronic effects of oral metoclopramide on gastric liquid emptying in 12 diabetic patients with symptoms of stasis using scintiscanning techniques. We found that liquid emptying in these subjects was abnormal, as determined by residue area determination when compared to normal volunteers (P less than 0.01). Metoclopramide 10 mg orally acutely enhanced emptying, restoring it to control values (P less than 0.01). In contrast, when gastric emptying was evaluated following one month of chronic liquid metoclopramide use, 10 mg before each meal, the acute effect of the drug on emptying could no longer be demonstrated and residue areas returned to baseline values, suggesting that chronic oral administration of metoclopramide may result in a loss of the gastrokinetic properties of this drug.

Drug utilization and morbidity statistics for the evaluation of drug safety in Sweden.

For a continuous monitoring and evaluation of drug safety problems in Sweden, the Department of Drugs of the National Board of Health and Welfare has access to a number of computerised patient-, drug-, and disease-oriented registers. The usefulness and limitations of these registers are presented by examples. A recent increase in asthma deaths is presently being analysed by comparing information from death certificates and case records with drug sales and prescription data. A recent analysis of the cancer register showed no increased risk of malignant thyroid tumors after diagnostic or therapeutic doses of I 131. Similarly no increased risk of malformations after occupational exposure to hexachlorophene could be detected by analysing the malformation and medical birth-record registers in relation to hospital hexachlorophene use. The register of patient discharge diagnoses has been repeatedly used to analyse the incidence and pattern of drug induced blood dyscrasias and thromboembolism associated with oral contraceptives (OC). These analyses have resulted i.a. in the withdrawal of dipyrone and tenalidine and a decrease of the estrogen-content of OCs. At the same time about 1/3 of these serious adverse drug reactions (ADR) was found to have been reported to the ADR-register. By combining sales and prescription data with ADR-reports the risk of inducing lactic acidosis was found to be significantly higher for phenformin than for metformin. Also the incidence of tardive dyskinesia from longterm use of metoclopramide was found to be much higher than hitherto recognized. By use of these registers it is possible to obtain valuable information about the safety of drugs. The raw data must, however, be interpreted with care and often be supplemented with in depth studies of the various problems.

Cisplatin, vindesine, and bleomycin chemotherapy of local-regional and advanced esophageal carcinoma

Seventy-one patients with epidermoid carcinoma of the esophagus were treated with a three-drug combination of cisplatin, vindesine, and bleomycin. Forty-five patients had local-regional tumor and received chemotherapy prior to surgery or radiation therapy. Twenty-six patients with extensive disease were treated primarily with chemotherapy alone. The overall major objective response rate to cisplatin-vindesine-bleomcyin was 53 percent (36 of 68 evaluable patients). Patients with local-regional disease had a higher response rate than those with extensive disease (63 and 33 percent, respectively). Following preoperative chemotherapy, 34 patients with local-regional disease underwent exploration. Resectable disease was present in 82 percent. There was no increase in operative morbidity or mortality (5.6 percent), when compared with historical control groups. The median survival for the preoperative chemotherapy group was 16.2 months, which is superior to that of a historical control group (p = 0.023). For patients with extensive disease, treated primarily with chemotherapy alone, the median duration of response was seven months. Toxicities of cisplatin-vindesine-bleomycin were in general well-tolerated, and included nausea and vomiting (seen less frequently because of extensive use of metoclopramide), alopecia, nephrotoxicity, and peripheral neuropathy. The dose-limiting toxicity was myelosuppression. Although conventional chemotherapeutic agents have little activity, these results indicate that the investigational combination of cisplatin, vindesine, and bleomycin can induce major regressions in a substantial proportion of patients with esophageal cancer. When this drug combination is used preoperatively, high resection rates and possibly improved survival are seen.

Effects of metoclopramide and bethanechol on delayed gastric emptying present in gastroesophageal reflux patients

Gastric emptying has been reported to be delayed in a significant percentage of patients with gastroesophageal reflux. The rationale for the use of metoclopramide and bethanechol in gastroesophageal reflux has been based on their ability to stimulate lower esophageal sphincter pressure and enhance acid clearance mechanisms. In this study, we investigated the comparative efficacies of metoclopramide and bethanechol in improving the rate of gastric emptying in gastroesophageal reflux patients in whom delayed emptying was present. Gastric emptying studies used an isotope-labeled mixed solid-liquid meal. Thirteen reflux patients with delayed gastric emptying received metoclopramide, 10 mg intramuscularly, and subcutaneous bethanechol, 0.07 mg/kg, in a randomized single-blind fashion. Eleven additional reflux patients with delayed gastric emptying received oral metoclopramide, 10 mg, in an open-labeled fashion. After parenteral metoclopramide, gastric emptying was significantly (p < 0.05) faster compared with both the initial basal day and the bethanechol treatment day. Compared with the normal gastric emptying rate established in 26 control subjects, metoclopramide accelerated gastric emptying into the normal range. Bethanechol did not increase gastric emptying. Metoclopramide orally also significantly improved gasric emptying. Our study indicates that metoclopramide, both parenterally and orally, increased the rate of gastric emptying in those reflux esophagitis patients in whom it was delayed, while bethanechol did not improve the degree of gastric retention in the same patients. Our results extend the rationale for the therapeutic efficacy of metoclopramide in gastroesophageal reflux disease.

Metoclopramide. A review of antiemetic trials.

Early clinical trials of metoclopramide at traditional doses failed to demonstrate protection against antineoplastic drug-induced vomiting, and its antiemetic potential for oncology patients was not re-examined until the unacceptable nausea and vomiting of the newly introduced cisplatin emphasised the need for improved supportive care. Repetition of the early studies with metoclopramide at usual doses (0.15 to 0.30 mg/kg) in cisplatin-induced emesis confirmed the lack of benefit for low dose therapy. However, on the basis of known pharmacodynamic data, metoclopramide was evaluated as an antiemetic in animal models, and a dose-related response was observed for cisplatin-induced emesis. After establishing safety in a phase I trial, rigorously controlled studies were conducted to assess the antiemetic potential of high dose metoclopramide in preventing cisplatin-induced emesis. Metoclopramide (2 mg/kg) was administered intravenously for a total of 5 doses during a 9-hour period beginning 30 minutes before administration of high-dose cisplatin (120 mg/m2). The results of 3 sequential trials established the superiority of metoclopramide over placebo, prochlorperazine, and tetrahydrocannabinol. Toxicity consisted of mild sedation, diarrhoea, and reversible extrapyramidal reactions. In no case was it necessary to discontinue metoclopramide because of adverse drug reactions. These encouraging results were rapidly followed by a series of pilot studies designed to extend the use of metoclopramide to other clinical situations. Intermediate dose metoclopramide (1 mg/kg for 6 doses) appeared effective particularly for emesis associated with lower doses of cisplatin (50 mg/m2 or less). The results of studies of short course metoclopramide (2 mg/kg for 3 doses) provided a promising alternative regimen for the outpatient setting. As with high dose metoclopramide, the toxicity of these two protocols was acceptable, manifesting as sedation, diarrhoea, and extrapyramidal reactions. Uncontrolled observations of continued metoclopramide treatment during subsequent courses of cisplatin suggest preservation of antiemetic efficacy, and preliminary results of studies of metoclopramide in non-cisplatin-containing regimens also suggest benefit. The combination of metoclopramide with other effective antiemetic agents may provide improved protection. These studies show how a rational approach based on preclinical observations can expand the usefulness of a drug at first thought ineffective in chemotherapy-induced emesis.

1 - The Aspiration Syndrome

Pulmonary aspiration of gastric contents poses a continuing hazard to obstetrical patients, resulting in needless loss of life in previously healthy women. Aspiration of significant volumes of acid, alkaline or food-containing gastric contents can cause serious morbidity and mortality. Efforts to reduce the incidence of this complication should be directed at: 1. Improved training of anaesthetic personnel in obstetric anaesthesia and use of more senior staff to cover obstetrical units. 2. Meticulous care in preanaesthetic evaluation of obstetrical patients to diagnose potential intubation problems. 3. More widespread use of regional anaesthesia for vaginal and caesarean delivery. 4. Administration of small doses of non-particulate antacids to obstetrical patients before anaesthesia. 5. Possible preoperative use of cimetidine or metoclopramide, or both.

Use of Metoclopramide in Preterm Infants

6 preterm infants with birth weights ranging from 790 to 1,040 g and gestational ages of 26-35 weeks were given metoclopramide at a mean postnatal age of 35 days. The infants were selected only after fulfilling rigid clinical criteria. All infants were spontaneously breathing and were on parenteral nutrition with 3% Vamin and 10% Neutralipid. Metoclopramide, 0.1 mg/kg/day, was given intravenously in three divided doses. Progress was monitored using abdominal girth, gastric residual aspirate before each feed, intestinal transit times, daily weight gain, number of episodes of vomiting or regurgitation and assessment of tolerance to increasing amounts of feeds. Excellent response was seen in all infants. Withdrawal of the drug led to prompt recurrence of all symptoms and signs which again disappeared on reinstitution of the medication. No untoward side-effects were noted during the administration of the drug. We conclude that, in selected cases, metoclopramide may be used for persistent functional feeding intolerance and gastric stasis.

Lower esophageal sphincter and the gastroesophageal antireflux mechanism.

AbstractVarious factors involved in the structure and functional control of the gastroesophageal antireflux mechanism were investigated experimentally in dogs and in a clinical series, with special attention to manometric examination of the lower esophageal sphincter (LES). The prevention of the compressive action of extrinsic paraesophageal structures did not lead to changes either in LES pressure or in LES response to increases in abdominal pressure. The mechanism intrinsic to the gastroesophageal junction, the LES, seems to be primarily responsible for the maintenance of gastroesophageal competence. Also, the LES response to increased ultra‐abdominal pressure appears to be a property of the LES itself. Vagotomy performed at different levels did not produce a change in LES pressure, whereas LES response was significantly attenuated after each type of vagotomy. The vagus nerves apparently have no important role in the maintenance of LES pressure, whereas LES response seems to be mediated by a vagal reflex. Intragastric bile instillation caused a significant rise in LES pressure, but chronic intragastric bile contamination did not lead to changes in gastroesophageal competence. This suggests that intragastric bile contamination does not have a deleterious effect on LES competence and does not seem to predispose to gastroesophageal reflux. Of the drugs generally used in premedication for or induction of anesthesia, atropine decreased LES pressure significantly. Metoclopramide, in turn, produced a significant rise in LES pressure and, when administered before atropine, was capable of preventing the depressant effect of atropine on LES pressure. Thus, routine use of metoclopramide in premedication for or induction of anesthesia to prevent the depressant effect of atropine on LES pressure and the possible consequent gastroesophageal reflux, pulmonary aspiration, and postoperative pulmonary complications should be considered. The mean LES pressure after surgery for reflux esophagitis was significantly greater in patients with an objectively good operative result than in those with an objectively poor result. However, some overlapping occurred in LES pressure values between these two groups. The correlation between LES manometry and other examination methods in the evaluation of the operative result of reflux esophagitis seems to be rather good.

The effect of metoclopramide, TRH and L-dopa on prolactin secretion in pituitary adenoma and in "functional" galactorrhoea syndrome.

The degree of autonomy in prolactin secreting pituitary adenomas and also prolactin secretory reserve in cases with suspected functional galactorrhea syndrome was evaluated with the use of metoclopramide, TRH and L-DOPA. It was found that in patients with pituitary adenoma the basal prolactin (PRL) level often exceeded 150 micrograms/l and the response to stimulation with TRH and/or metoclopramide was markedly diminished or even nonexistent, while the response to L-DOPA was usually retained. In patients with galactorrhoea and/or amenorrhoea, with normal skull X-ray the basal PRL level was either normal or moderately raised but the response to stimulation was various; mostly it was excessive, it was sometimes normal, but in some other cases it was markedly diminished as in patients with adenoma. In the author's opinion the so-called "functional disorder" of prolactin secretion is mainly hyperresponsiveness to stimulation, whereas the basal PRL level in those cases is usually normal or only intermittently raised. In the cases with a moderate hyperprolactinaemia, especially if it appears to be constant, and the response to stimulation is diminished or none at all, we suspect a pituitary microadenoma. Finally, there are rare cases of galactorrhoea with normal basal PRL and normal response to stimulation, in which the sensitivity of the mammary PRL receptor is probably increased. We suggest therefore that the above mentioned PRL stimulation tests may help in distinguishing between tumoural and functional hyperprolactinaemia.

The use of metoclopramide in the prevention of postoperative paralytic ileus: A randomized double blind study

The use of metoclopramide in the prevention of postoperative paralytic ileus: A randomized double blind study

Anaesthesia Induction and Lower Oesophageal Sphincter Pressure

The effects of some drugs generally used in premedication for and induction of anaesthesia on the lower oesophageal sphincter (LOS) pressure were investigated in 30 dogs, using the modern oesophageal manometric technique. In thiopental-induced anaesthesia, a distinct pressure gradient was noted between the LOS and gastric pressure. Atropine eliminated this pressure gradient almost completely. Metoclopramide increased the LOS pressure significantly, and subsequent atropine administration was unable to bring it down. Metoclopramide administered after atropine was unable to elevate the LOS pressure reduced by atropine. Succinylcholine had no observable lasting effect on the LOS pressure. The present findings seem to indicate that of the drugs generally used in premedication for and induction of anaesthesia, atropine significantly reduces the LOS competence, thereby creating favourable conditions for gastro-oesophageal reflux (GOR) and consequent postoperative pulmonary complications. Use of metoclopramide in premedication for or induction of anaesthesia to eliminate the depressant effect of atropine on the LOS pressure appears to be indicated.

The Use of Metoclopramide in the Elderly

118 patients receiving metoclopramide for a variety of symptoms were studied. The drug was effective in relieving nausea and vomiting caused by centrally acting emetics such as morphine and digitalis. It was also effective when these symptoms were due to locally acting factors in the upper gastro-intestinal tract, such as peptic ulcer. Rapid relief of post-influenzal depression, and associated nausea and vomiting was also obtained. Three patients with hiccup were rapidly relieved. Very little relief of anorexia was obtained in patients suffering from carcinoma of the gastro-intestinal tract or other organs.

The use of oral Metoclopramide in the barium meal and follow-through examination.

Metoclopramide given orally in a dose of 20 mg three to ten minutes prior to a barium meal and follow-through examination is an effective hurrying agent allowing routine follow-through examinations to be undertaken with a minimum of extra films or radiation. The more rapid emptying of the stomach allows immediate visualisation of the duodenal cap and loop and does not appear to interfere with the diagnostic quality of the films so obtained. Apart from the increase in the number of contracted segments there was no detectable difference in the pattern of the small bowel or its calibre, which was displayed down to the terminal ileum within 75 minutes in the vast majority of cases. No untoward side effects were detected in patients taking 20 mg of Metoclopramide orally prior to a barium meal. Lesions such as diverticula and those associated with Crohn's disease were clearly visible.

Modification to the technique for small bowel biopsy in children including the use of metoclopramide.

SMALL BOWEL mucosal biopsy in children using a modified Crosby capsule has been an unsatisfactory investigatory technique in our hands because of the uncertainty of the capsule passing through the pylorus. The procedure carried a very high failure rate in the children between 2 and 5 years of age, and a high success rate in children over the age of 5 years. This experience is very similar to that reported by Sheldon and Tempany. 1 The length of time required for each procedure has been considerable and the lack of control over the inserted capsule using a flexible tube had been a problem. Previously we have not been able to fix to the capsule a tube which is firm and capable of being manipulated. Metoclopramide hydrochloride (4-amino-5-chloro-N-[2-(diethylamino) ethyl]-o anisamide hydrochloride) has been shown to increase gastric peristalsis in several studies including those of Grivaux et al 2 Tourneur et