Recurrent syncope, hypotension, asthma, and migraine with aura: role of metoclopramide

Migraine associated with asthma or symptomatic orthostatic hypotension is a particularly difficult subgroup to manage. Metoclopramide is a useful pharmacological agent for orthostatic hypotension. I present the case report of a migraine patient with asthma and recurrent hypotensive syncope. Metoclopramide relieved recurrent syncope as well as migraine attacks in this patient. Metoclopramide has a striking influence on arginine vasopressin (AVP) secretion. AVP promotes antinociception and influences vasomotor and behavior control, which actions possibly keep migraine in remission. Further studies are necessary to confirm the migraine prophylactic value of metoclopramide.     

The effects of metoclopramide in modifying the response of isolated guinea-pig ileum to various agonists.

Metoclopramide has a dual effect on intestinal smooth muscle. Low concentrations of metoclopramide cause potentiation of the responses to substance P, acetylcholine, histamine and barium chloride on the guinea-pig ileum. Higher concentrations produce a depression of smooth muscle responses which is characteristic of the tertiary amine local anesthetics. Neural pathways are involved in the mechanism of potentiation, since the enhancement of the responses to the agonists is abolished by tetrodotoxin. Atropine partially antagonizes the potentiating effect of metoclopramide implying that activation of muscarinic receptors is a contributing factor, but this does not fully explain the potentiation.     

Metoclopramide kinetics in patients with impaired renal function and clearance by hemodialysis

Metoclopramide kinetics were examined in 24 adult patients with diminished renal function and in eight healthy subjects with normal renal function. Creatinine clearance correlated with metoclopramide plasma clearance, renal clearance, nonrenal clearance, and elimination t1/2. Regardless of renal function, renal clearance accounted for less than or equal to 21% of total plasma clearance. Nonrenal clearance was reduced in patients and accounted for most of the reduction in plasma clearance. The comparatively small plasma clearances in patients imply that maintenance doses should be reduced accordingly to avoid drug cumulation. Metoclopramide clearance by hemodialysis was also assessed in four patients. Metoclopramide losses from hemodialysis were relatively small compared to estimates of total body metoclopramide stores. Compensatory dosage increases are probably unnecessary for most patients. These data also suggest that hemodialysis is not likely to be effective in metoclopramide overdose.     

Relationship of serotonin-3 receptor antagonist activity to gastric emptying and motor-stimulating actions of prokinetic drugs in dogs

Drugs that enhance gastrointestinal motility include the benzamide drugs metoclopramide, cisapride and renzapride (BRL-24924). Because these agents also are serotonin-3 (5-HT3) receptor antagonists, which can promote gastric emptying in some species, the motor-stimulating properties of benzamide agents may be due to this mechanism. Metoclopramide (0.3-3.0 mg/kg i.v.), cisapride (0.03-1.0 mg/kg i.v.) and BRL-24924 (0.01-0.1 mg/kg i.v.) were evaluated for their relative motility-stimulating and 5-HT3 receptor antagonist activities in conscious dogs and were compared with selective 5-HT3 antagonist antiemetic compounds ICS-205-930, (3 alpha-tropanyl)1-H-indole-3-carboxylic acid ester and granisetron (BRL-43694). Gastric antral contractions and intestinal myoelectric motility were determined in response to drugs, as were their effects on solid and liquid emptying in a gamma scintigraphic model of gastroparesis. 5-HT3 receptor antagonist potency was examined by deriving ED50 values for inhibition of cisplatin emesis. All drugs were 5-HT3 antagonists as they blocked cisplatin emesis with relative potencies of BRL-43694 = ICS-205-930 greater than BRL-24924 greater than cisapride = metoclopramide. The order of potency for stimulating fasted dog antral contractile activity, however, was BRL-24924 = cisapride greater than metoclopramide greater than ICS-205-930 = BRL-43694. Maximally effective doses of BRL-24924 (0.1 mg/kg i.v.) and cisapride (0.67 mg/kg i.v.) in the antrum also stimulated intestinal myoelectrical activity, whereas ICS-205-930 (0.5 and 2.0 mg/kg i.v.) was not active.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metoclopramide improves gastric motility in critically ill patients

Objective: To assess the effect of metoclopramide on gastric motility in critically ill patients. Design: Prospective, controlled, single-blind cross-over trial. Setting: A 10-bed general intensive care unit. Patients: Ten critically ill, enterally fed adult patients without renal failure. Interventions: Each patient received enteral feeding with Enrich via a nasogastric tube at 50 ml/h throughout the 5-h study period on two consecutive days. Either normal saline (control) or 10 mg of metoclopramide (treatment) was administered intravenously at the start of the study period in random order with cross-over design. Measurements and results: Gastric motility was measured indirectly by analysis of the absorption over time of 1.5 g of paracetamol administered into the stomach at the start of the study period together with a 100 ml bolus of Enrich feed. The rate of gastric emptying is proportional to the area under the line plot of serum paracetamol concentration against time over 120 min (AUC120). Eight of the ten patients studied showed an increased AUC120 with metoclopramide compared to that with saline. Statistical analysis with the Wilcoxon signed rank test gave a p value of 0.04, indicating a significant increase in gastric emptying following administration of metoclopramide. Conclusions: The administration of intravenous metoclopramide improved gastric emptying in a heterogeneous group of critically ill patients. Metoclopramide is a useful prokinetic drug in this patient population. Final revision received: 18 January 1999 Accepted: 2 March 1999     

Diagnosing motility disorders of the upper gastrointestinal tract

The past decade has witnessed an exponential growth of knowledge about upper gastrointestinal motility. The elucidation of the clinical problems is based on remarkable morphophysiologic, clinical, diagnostic, and pharmacotherapeutic advances. New approaches rely on a more sensitive application of manometric evaluation which has allowed identification of more subtle abnormalities of motility, as well as appreciation of the role of scintigraphic studies to measure transit through the esophagus, combined with the standard use of the cine-esophagogram modified to assess a solid bolus. New techniques to evaluate gastric motility include myoelectric gastrography and administration of isotope-labeled meals. These advances have been enhanced by the advent of prokinetic therapeutic agents, such as metoclopramide and domperidone. Evaluation of intestinal motility involves the use of intraluminal pressure sensing catheters, as well as methods to measure transit times. The standard hydrogen breath test as a noninvasive study of small intestinal transit time has been supplemented by an isotope-labeled liquid meal. Identification of clinical states with delayed and rapid small bowel transit times will have therapeutic implications in the future.     

Chronic metoclopramide therapy for diabetic gastroparesis

OBJECTIVE: To review the safety and efficacy of chronic metoclopramide for diabetic gastroparesis. DATA SOURCES: Medical literature was accessed through MEDLINE (1965 to October 2002) and PubMed (1965 to October 2002). Key search terms included metoclopramide; diabetic gastroparesis; and dyskinesia, drug induced. DATA SYNTHESIS: Metoclopramide is often used for diabetic gastroparesis, despite the risk of tardive dyskinesia. Published information is limited regarding long-term efficacy and toxicity of metoclopramide. The literature was assessed concerning these topics. CONCLUSIONS: Limited data do not provide sufficient evidence to conclude whether metoclopramide is efficacious for chronic use. Routine monitoring may mitigate the risk associated with metoclopramide therapy.     

Sequential single doses of cisapride, erythromycin, and metoclopramide in critically ill patients intolerant to enteral nutrition: a randomized, placebo-controlled, crossover study

OBJECTIVE: To evaluate the comparative efficacy of enteral cisapride, metoclopramide, erythromycin, and placebo for promoting gastric emptying in critically ill patients with intolerance to gastric enteral nutrition (EN). DESIGN: A randomized, crossover study. SETTING: Adult medical intensive care unit at a university-affiliated private hospital and trauma intensive care unit at a university teaching hospital. PATIENTS: Ten adult, critically ill, mechanically ventilated patients not tolerating a fiber-containing EN product defined as a single aspirated gastric residual volume >150 mL or two aspirated gastric residual volumes >120 mL during a 12-hr period. INTERVENTIONS: Patients received 10 mg of cisapride, 200 mg of erythromycin ethylsuccinate, 10 mg of metoclopramide, and placebo as 20 mL of sterile water every 12 hrs over 48 hrs. Acetaminophen solution (1000 mg) was administered concurrently. Gastric residual volumes were assessed, and plasma acetaminophen concentrations were serially determined by TDx between 0 and 12 hrs to evaluate gastric emptying. MEASUREMENTS AND MAIN RESULTS: Gastric residual volumes during the study were not significantly different between agents. No differences in area under the concentration vs. time curve or elimination rate constant were identified between agents. Metoclopramide and cisapride had a significantly shorter mean residence time of absorption than erythromycin (6.3+/-4.5 [SEM] mins and 10.9+/-5.8 vs. 30.1+/-4.5 mins, respectively [p<.05]). Metoclopramide (9.7+/-15.3 mins) had a significantly shorter time to peak concentration compared with erythromycin and placebo (60.7+/-8.1 and 50.9+/-13.5 mins, respectively [p<.05]). The time to onset of absorption was significantly shorter for metoclopramide vs. cisapride (5.7+/-4.5 vs. 22.9+/-5.7 mins [p<.05]). CONCLUSION: In critically ill patients intolerant to EN, single enteral doses of metoclopramide or cisapride are effective for promoting gastric emptying in critically ill patients with gastric motility dysfunction. Additionally, metoclopramide may provide a quicker onset than cisapride.     

Metoclopramide versus hydromorphone for the emergency department treatment of migraine headache.

We conducted a retrospective cohort study to compare the effects of metoclopramide versus hydromorphone for the initial emergency department treatment of migraine headache at an urban teaching hospital. The primary outcome measure was the mean difference in the subjects' self-reported pain scores before and after the administration of the initial medication treatment. We also estimated crude and adjusted relative risks (using Poisson multivariate regression modeling) to assess and control potential confounding by age, gender, race, and pain score before initial medication. Two hundred subjects were included, with 51 (25.5%) receiving intravenous or intramuscular hydromorphone, 95 (47.5%) receiving intravenous metoclopramide, and 54 (27.0%) receiving 1 of several other medications. Using a standardized pain scale of 0 to 10, mean pain score reductions were 2.3 points for hydromorphone, 3.7 points for metoclopramide, and 2.8 points for all other medications combined (P < .001). When comparing metoclopramide versus hydromorphone, the crude relative risk for pain reduction of 3 or more points was 1.76 (95% CI, 1.12-2.75, P = .01), and the adjusted relative risk was 1.60 (95% CI, 0.84-3.03, P = .15). Metoclopramide also resulted in less use of rescue medications, faster times to discharge, and no difference in the frequency of adverse reactions. PERSPECTIVE: Metoclopramide appears to be an effective initial medical treatment for migraine headaches in the emergency department setting, but its pharmacologic mechanism remains incompletely understood. A double-blinded, randomized, controlled trial comparing standard dosages of hydromorphone versus metoclopramide will be needed to definitively determine which medication is more effective.     

The antiemetic activity of high-dose alizapride and high-dose metoclopramide in patients receiving cancer chemotherapy: a prospective, randomized, double-blind trial

Alizapride is a new substituted benzamide with suggested superior antiemetic efficacy to and fewer side effects than metoclopramide. High-dose alizapride (4 mg/kg X five doses) was compared with high-dose metoclopramide (2 mg/kg X five doses) in a prospective, randomized, double-blind trial in 62 evaluable patients undergoing strongly emetic cancer chemotherapy. Patients receiving metoclopramide experienced significantly fewer vomiting episodes than patients receiving alizapride (median of three episodes vs. eight episodes; P less than 0.001). Metoclopramide was more effective in decreasing the volume of emesis than was alizapride (median of 100 ml vs. 360 ml; P less than 0.02). Seventy-two percent of the patients receiving alizapride and 57% of those receiving metoclopramide experienced side effects. High-dose metoclopramide is an effective antiemetic in patients receiving cancer chemotherapy. Alizapride is less effective and has more side effects than metoclopramide. We do not recommend the further use of alizapride.     

Domperidone: a peripherally acting dopamine2-receptor antagonist

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of domperidone in the treatment of gastrointestinal motility disorders and emesis. DATA SOURCES: MEDLINE and Excerpta Medica online databases were searched to identify published reports. STUDY SELECTION: Domperidone has been marketed worldwide outside the US since 1978, and extensive clinical data for this drug are available. This review focuses on the clinical experience from controlled studies of domperidone in the treatment of motility disorders, particularly diabetic gastroparesis. Also, case reports are used in summarizing safety. The control comparator groups included placebo or other prokinetic drugs (metoclopramide and cisapride). Controlled clinical trials of domperidone's efficacy and safety as an antiemetic are also briefly examined. Although a variety of domperidone dosage forms have been marketed, data generated from trials using the 10-mg tablet are highlighted because this is the only dosage form available in Canada and is under investigation in the US. DATA EXTRACTION: Because symptoms do not correlate with objective measures of gastrointestinal motility and they are the primary reason that patients with motility disorders seek treatment, the primary outcome extracted from the clinical studies was symptomatic response to treatment. Safety and efficacy between domperidone and placebo, metoclopramide, or cisapride were compared. DATA SYNTHESIS: Domperidone, a peripheral dopamine2-receptor antagonist, regulates the motility of gastric and small intestinal smooth muscle and has been shown to have some effects on the motor function of the esophagus. It also has antiemetic activity as a result of blockade of dopamine receptors in the chemoreceptor trigger zone. In controlled clinical trials, domperidone provided better relief of symptoms (anorexia, nausea, vomiting, abdominal pain, early satiety, bloating, distension) than placebo in patients with symptoms of diabetic gastropathy; symptomatic improvement was similar with domperidone and metoclopramide or cisapride. Domperidone also provided short-term relief of symptoms in patients with dyspepsia or gastroesophageal reflux, prevented nausea and vomiting associated with emetogenic chemotherapy, and prevented the gastrointestinal and emetic adverse effects of antiparkinsonian drugs. Because very little domperidone crosses the blood-brain barrier, reports of central nervous system adverse effects, such as dystonic reactions, are rare. CONCLUSIONS: Domperidone is a unique gastrokinetic and antiemetic drug. Because of its favorable safety profile, domperidone appears to be an attractive alternative to metoclopramide. In the management of diabetic gastropathy, domperidone's antiemetic activity distinguishes it from cisapride.     

Unaltered dopaminergic modulation of aldosterone secretion in cirrhosis

1. The responses of plasma aldosterone and plasma prolactin concentrations to metoclopramide (10 mg intravenously) were evaluated over 2 h in eight healthy controls and in 23 patients with cirrhosis (10 without and 13 with ascites). Plasma renin activity, glomerular filtration rate and renal sodium excretion were also determined. 2. Metoclopramide did not significantly influence plasma renin activity, whereas both plasma aldosterone and plasma prolactin rose significantly. The incremental areas under the curves did not differ among controls and cirrhotic patients without and with ascites. No significant correlations between plasma prolactin and aldosterone, either under basal conditions or after metoclopramide administration, were found in either controls or patients. 3. Glomerular filtration rate did not change after metoclopramide. Renal sodium excretion in controls and cirrhotic patients without ascites was also unaffected, whereas it decreased significantly in cirrhotic patients with ascites. In the latter, renal sodium excretion was inversely correlated with plasma aldosterone both under basal conditions and after metoclopramide administration. 4. The dopaminergic control of aldosterone secretion does not appear to be significantly altered in cirrhosis. Metoclopramide administration to cirrhotic patients with ascites leads to an increase in plasma aldosterone that may enhance renal sodium retention.     

Comparison of cisapride and metoclopramide for facilitating gastric emptying and improving tolerance to intragastric enteral nutrition in critically III, mechanically ventilated adults.

BACKGROUND: Placebo-controlled studies have indicated that both cisapride and metoclopramide promote gastric motility in critically ill patients. Objective: This study was conducted to compare cisapride and metoclopramide for facilitating gastric emptying and improving tolerance to intragastric enteral nutrition (EN) and to evaluate the relationship between aspirated gastric residual volume and gastric emptying function in this patient population. METHODS: In this double-blind study, critically ill, mechanically ventilated patients with an aspirated gastric residual volume > or = 150 mL while receiving intragastric EN were randomized to receive enteral cisapride 10 mg or metoclopramide 10 mg every 6 hours for a total of 7 doses. The acetaminophen-absorption method was used to assess gastric emptying at baseline and 30 minutes after the seventh dose by determining the area under the plasma concentration-time curve at 240 minutes (AUC240), maximum concentration (Cmax), and time to Cmax (Tmax). Gastric residual volume was measured every 6 hours before dosing. RESULTS: Fourteen patients were included in the study, 7 in each group. Patient characteristics were similar in the 2 groups. Compared with baseline, metoclopramide significantly accelerated Tmax (39.00 +/- 15.56 min with metoclopramide vs 103.71 +/- 47.35 min at baseline; P = 0.018) and increased Cmax (12.94 +/- 6.68 mg/L vs 6.97 +/- 4.78 mg/L; P = 0.018) and AUC240 (1,421.43 +/- 780.31 mg/L x min vs 839.00 +/- 545.58 mg/L x min; P = 0.043). Cisapride increased Cmax from baseline (12.27 +/- 8.95 mg/L vs 4.53 +/- 2.37 mg/L, respectively), but the difference was not statistically significant. Gastric residual volume was significantly reduced from baseline after 3 doses of metoclopramide (from 268.7 +/- 112.3 mL to 57.0 +/- 23.1 mL; P < 0.05) and was significantly lower after the seventh dose of metoclopramide than after the seventh dose of cisapride (5.3 +/- 8.2 mL vs 41.4 +/- 39.7 mL, respectively; P = 0.05). Cmax at baseline and residual volume at study entry were inversely correlated (r = -0.50; P = 0.049). Conclusions: Both cisapride and metoclopramide enhanced gastric motility and improved tolerance to intragastric EN. Metoclopramide reduced gastric residual volume to a significantly greater extent than did cisapride. Only Cmax at baseline was inversely associated with residual volume.     

Tolfenamic acid and caffeine: A useful combination in migraine

Tolfenamic acid is a potent inhibitor of prostaglandin biosynthesis, which has been proved effective in the treatment of acute migraine attacks. The usefulness of caffeine, metoclopramide and pyridoxine as adjuncts to tolfenamic acid was tested in acute migraine attacks in ten patients. A combination of tolfenamic acid (200 mg) with either caffeine (100 mg), metoclopramide (10 mg) or pyridoxine (300 mg) was given twice to each patient in random order. Thus 60 attacks were treated. The tolfenamic acid-caffeine combination proved the most effective as judged by duration and intensity of attacks, working ability, vigilance, and overall evaluation of the drugs by the patients. Metoclopramide was somewhat better than pyridoxine as an additive.     

Effect of metoclopramide on dopamine-induced changes in renal function in healthy controls and in patients with renal disease

1. The effects of intravenous metoclopramide on baseline values and dopamine dose-response curves for renal haemodynamics and natriuresis were investigated in healthy volunteers and patients with renal disease. 2. Dopamine infusion alone, in doses ranging from 0.25 to 8 micrograms min-1 kg-1, resulted in a dose-dependent increase in effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) with a fall in filtration fraction (FF) in eight hydrated healthy volunteers and, to a lesser degree, in 12 patients with renal disease. An increase in natriuresis (urinary excretion of sodium, UNa+V), fractional excretion of sodium (FENa+) and diuresis (urine flow rate, UV) was found in both groups for doses of 2 micrograms min-1 kg-1 and higher. 3. Metoclopramide infusion did not alter baseline values of GFR, ERPF or FF, but shifted the dopamine dose-response curve for ERPF and FF in the healthy volunteers. Metoclopramide induced a fall in UNa+V and FENa+ in both groups (fall in baseline FENa+ from 1.52 to 0.71 during metoclopramide in healthy volunteers and from 1.23 to 0.56 in patients; P less than 0.01) and blunted the natriuretic response to subsequent dopamine infusion. The fall in UNa+V during metoclopramide infusion showed a strong correlation with baseline GFR (r = -0.944). In the patients, the response for the fractional excretions of beta 2-microglobulin and gamma-glutamyltransferase was comparable with that of FENa+. 4. Dopamine infusion induced a fall, and metoclopramide led to rise, in plasma aldosterone concentration. 5. We conclude that metoclopramide acts as a dopamine antagonist at the renal level in man.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevention of meal-induced heartburn and regurgitation with metoclopramide in patients with gastroesophageal reflux

Ten patients with gastroesophageal reflux disease participated in a randomized, double-blind, crossover study in which they received a single 20-mg oral dose of metoclopramide or a placebo 15 minutes before a provocative test meal. All patients had previously been challenged with the test meal and had exhibited symptoms of heartburn and regurgitation. Metoclopramide reduced the severity of heartburn from the onset, its effect reaching statistical significance within two hours and persisting for at least five hours. Eighty percent of the patients who received metoclopramide, compared with only 30% of placebo-treated patients, were completely free of heartburn at the end of the trial. A significant reduction in regurgitation during the 1 1/2 to four hours after the test meal was also noted with metoclopramide. No adverse effects occurred. The ability of metoclopramide to prevent the symptoms of heartburn and regurgitation induced by a provocative meal in patients with gastroesophageal reflux was clearly demonstrated.     

The influence of neostigmine and metoclopramide or their combination on gastric emptying

The effect of a neostigmine-mediated increase in acetylcholine and its influence on metoclopramide's effect on gastric emptying was studied in six healthy volunteers by using the Wagner-Nelson method of calculating the fraction of paracetamol absorbed. Gastric emptying was not significantly influenced by metoclopramide, but the combination of metoclopramide and neostigmine had an effect similar to that of neostigmine alone. Metoclopramide did not significantly slow the “hurrying” effect of neostigmine.     

Randomized, double-blinded, placebo-controlled trial of ondansetron plus dexamethasone with or without metoclopramide as antiemetic prophylaxis in patients receiving high-dose cisplatin in medical practice

Purposes  

Ondansetron plus dexamethasone are standard antiemetic agents for highly emetogenic chemotherapy. Metoclopramide is a dopamine antagonist, which may enhance efficacy of ondansetron and dexamethasone. The objective of this study was to assess the efficacy and tolerability of metoclopramide added to standard antiemetic regimen for prophylaxis of cisplatin-induced emesis.     

Ergotamine vs. metoclopramide vs. their combination in acute migraine attacks

The effect of ergotamine tartrate was compared with that of the antiemetic agent metoclopramide and with those of two combinations in a double-blind trial of 24 adult female patients with migraine. The following combinations of the drugs were used in oral administration in a total of 176 acute migraine attacks: (a) Ergotamine 1 mg, (b) Metoclopramide 20 mg, (c) Ergotamine 1 mg + metoclopramide 20 mg, (d) Ergotamine 2 mg + metoclopramide 20 mg. The duration of attacks was significantly shorter on both of the combinations compared with the single drugs. The intensity of the pain was somewhat weaker and the appearance of nausea and vomiting somewhat but not significantly less during the combination treatments. In their overall opinion the patients favored the 2 mg + 20 mg combination significantly more than the others. Both ergotamine and metoclopramide are efficient in acute migraine attacks. Their combination seems to enhance the therapeutic response in some respects.