Promotility Agents Research Articles

Metoclopramide and Homicidal Ideation: A Case Report and Literature Review

Metoclopramide is an anti-emetic and gastrointestinal pro-motility agent associated with well-known neuropsychiatric adverse effects, such as dyskinesia, akathisia, and depression. It has never been reported to be associated with homicidal ideation. The authors review the literature on metoclopramide-induced adverse neuropsychiatric reactions and the mechanisms by which these may occur. The authors present a case report of a patient who developed anxiety, agitation, suicidal and homicidal ideation following brief exposure to metoclopramide. The adverse effects of agitation and homicidal ideation were temporally related to the starting and stopping of metoclopramide. The patient subsequently developed agitation without homicidal ideation when given a serotonergic antidepressant a week later, suggesting that serotonin handling may have played a significant role in causing the patient's symptoms. Although metoclopramide is well-known for its side effects related to dopamine blockade, its action at 5-HT₃ and 5-HT₄ receptors may also be clinically significant in the genesis of neuropsychiatric side effects, especially related to mood and behavior.

Impact of Pharmacotherapy on Interstage Outcomes in Single Ventricle Infants

To characterize the pharmacotherapeutic regimens used in infants with single ventricle heart disease and determine the influence of outpatient medications on interstage weight gain. Retrospective review. Tertiary care pediatric hospital. All patients discharged from our institution with single ventricle heart disease that underwent neonatal first stage surgical palliation between 2002 and 2009 were included. Patients who died prior to second stage palliation or underwent orthotopic heart transplantation were excluded. Outpatient medication regimens during the interstage period were reviewed. Medication regimens were compared between surgical eras and between patient groups experiencing different outcomes. A logistic regression model was developed to determine independent factors for an interstage increase in weight-for-age z-score (WAZ) and a linear regression model to determine medications significant for an increase in weight gain per day. The study cohort consisted of 161 patients (58% male). Most patients in this cohort had either hypoplastic left heart syndrome (51%) or unbalanced complete atrioventricular canal (29%). Patients were placed on a median of four medications (range 1-9) at discharge from first surgical palliation, with aspirin (79%), furosemide (79%), and angiotensin converting enzyme inhibitors (ACE-I) (73%) most commonly prescribed. A median of six medication doses per day (range 2-18) were prescribed at discharge. Most patients (71%) had a decrease in WAZ during the interstage period. Use of digoxin (P < 0.01) and high-dose furosemide (P = .02) were associated with a decrease in WAZ score during the interstage period. Additionally, the use of ACE-I, ranitidine, proton-pump inhibitors, or promotility agents was not associated with improved somatic growth during the interstage period. Infants with single ventricle heart disease have a high-medication burden during the interstage period. Despite the focused and intensified use of medications to improve feeding tolerance and somatic growth, current pharmacotherapeutic regimens appear to have little effect on interstage weight gain.

Prokinétiques chez le patient de réanimation : quand et lesquels ?

Despite the well-known advantages of enteral nutrition in intensive care patients, a delay in gastric emptying is often observed and precludes delivery of full nutritional support by the enteral route. This article focuses on the place and choice of digestive promotility agents for improving tolerance of enteral nutrition during critical illness. A comprehensive and individualized approach is proposed.

Pharmacotherapy for Gastroparesis: An Attempt to Evaluate a Safer Alternative

Pharmacotherapy for Gastroparesis: An Attempt to Evaluate a Safer Alternative

Colonic Ischemia in a Young Patient: Who To Blame?

Purpose: Case Presentation: A 37 year old female presented to clinic for evaluation of rectal condylomata by colonoscopy. Patient was given bisacodyl and polyethylene glycol bowel prep (halflytely) one day prior to the procedure. Patchy erythema was noted in the sigmoid colon 20 to 30 cm from the anal verge. Biopsy of the affected area was consistent with ischemic colitis (IC). The patient returned in six months for repeat colonoscopy and was given the same bowel preparation. Mucosal changes and histologic biopsies were again consistent with ischemic colitis in the same area. The patient was not on any medication. Additionally, hypercoaguable work up was negative. Discussion: Numerous medications have been shown to cause IC. Evidence linking bisacodyl and polyethylene glycol (PEG) to IC has been suggested yet rarely studied. Though the mechanism of action of bisacodyl is not entirely known, it seems to act at two levels. The first is as a stimulant of peristalsis and the second to promote fluid and ion accumulation in the lumen. Few mechanisms have been proposed linking bisacodyl to IC. Bisacodyl may cause rapid fluid shifts to the gut lumen causing transient hypoperfusion and ischemia. This may also be the mechanism behind IC and PEG. PEG is also believed to be an osmotic agent, though it has been rarely implicated as a cause for IC. One study, however, found patients with IC during PEG interferon alpha and ribavarin therapy. Another case showed a young adult with transient ischemic colitis after PEG and glycerin enema. Alternatively, bisacodyl may cause diminished blood flow to the colon by inducing both increased motility and pressure. This latter mechanism may also be the reason IC has been linked to tegaserod use, lending further credence to the association between promotility agents and IC. Our patient had no known risk factor for IC. Additionally, IC is rare in young adults. It is these factors that favor the assertion that the bowel preparation caused IC in our patient. Conclusion: Bowel preparation may be an under recognized source of IC. This case illustrates that bowel preparations are a plausible risk factor for IC, particularly in the young adult. Large studies are lacking, making this a promising area future research.

Effects of Orally Disintegrated Metoclopramide (ODM) in Optimizing Late Outpatient Endoscopy: A Randomized Double-Blind Placebo-Controlled Clinical Trial

Purpose: Outpatient endoscopy is a standard procedure. Six hours fasting for solids and two hours for liquids are standard anesthesia guidelines prior to sedation. This study evaluates the beneficial effects of ODM, a promotility agent, given 20 minutes prior to the procedure in the late afternoon with five hours post lunch interval. Methods: 129 patients (age: 25-75 years) were randomized into three arms. Arm A (n=43): ODM 10 mg 20 minutes before endoscopy in the late afternoon; Arm B (n=43): oral Metoclopramide 10 mg 30 minutes before endoscopy; Arm C (N=43): the placebo. The last solid meal was given at noon (one oz. of either chicken, turkey, or tuna with half an oz. of potato or fruits salads, without mayonaise or dairy products, and 12 oz. of water) five hours before endoscopy. The Anesthesiologist administered routine IV Propofol with documented pre- and post-sedation time. The total time of panendoscopy with six biopsies and recovery time were evaluated. Exclusions: active GI bleeding, DM, BMI>33, neuromuscular diseases, known gastric motility disorders, gastric malignancy, and drugs altering GI motility. Results: The total sedation time was similar (p=0.91) between the ODM (5.1±0.9 minutes; mean±SD) and oral Metoclopramide (5.6±1.4 minutes) groups; both groups were significantly shorter (p<0.001) than the placebo (12.6±3.4 minutes; p<0.001, one-way ANOVA). Likewise, the recovery time was comparable (p=0.75) between the ODM (11.7±4.3 minutes) and oral Metoclopramide (10.9±4.4 minutes) groups, with both being significantly shorter (p<0.001) than the placebo (27.9±6.5 minutes; p<0.001, one-way ANOVA). No major side effects were observed in the ODM group, while dizziness and confusion occurred in both the oral Metoclopramide (n=11 and 7) and placebo (n=20 and 12) groups. Conclusion: The use of ODM in outpatient endoscopy is beneficial over standard endoscopy with reduced amount of sedation, prompt recovery, and wider safety profile. A multicenter trial is needed to validate these findings.

Utilisation des médicaments prokinétiques en réanimation : indications et limites ?

Enteral feeding is often limited by gastric and intestinal motility disturbances in critically ill patients, particularly in patients with shock. So, promotility agents are frequently used to improve tolerance to enteral nutrition. This review summaries the pathophysiology, presents the available pharmacological strategies, the clinical data, the counter-indications and the principal limits. The clinical data are poor. No study demonstrates a positive effect on clinical outcomes. Metoclopramide and erythromycin seems to be the more effective. Considering the risk of antibiotic resistance, the first line use of erythromycin should be avoided in favor of metoclopramide.

Upper gastrointestinal promotility drugs: not all uniform?

The pathophysiology of functional gastrointestinal (GI) disorders has been under broad investigation in the past two decades; dysmotility remains one of the main focuses of the research. Numerous studies have documented abnormal gastroduodenal motility in patients with functional dyspepsia, irritable bowel syndrome, and other functional GI disorders. In functional dyspepsia, the abnormalities range from delayed to accelerated gastric emptying, abnormal antral and fundic contractions, and disordered accommodation in the fundus and antrum. Some of the functional GI symptoms may be explained by disturbed motility both during and after the meal. Less is known about small bowel dysmotility. Alterations in small bowel transit time, proximal small bowel accommodation, and abnormal contractions may play a role in pathophysiology of symptoms of the functional disorders. Currently, we have witnessed rapidly accumulating knowledge about the functional characteristics of GI tract motility. Some new tools are available such as a wireless motility capsule 1 or impedance pH test. These tests can give additional information about the relationships between GI transit and contractility as measured by manometry. But antroduodenal manometry, though uncommonly performed, still provide fascinating insights into upper GI motility. Using promotility agents to treat functional GI disorders is very attractive, given that they may target some of the underlining pathophysiologic mechanisms. Unfortunately, most of them are only modestly effective. This may be due to the fact that normal gut motility is a complex interaction between multiple neurotransmitters, while available drugs usually target only one neurotransmitter or receptor involved in the maintaining of normal GI motility function.

A case of severe, refractory diabetic gastroparesis managed by prolonged use of aprepitant

A 31-year-old woman with an 11-year history of poorly controlled type 1 diabetes mellitus was admitted with severe vomiting and ketoacidosis. The patient had been admitted to hospital on 14 occasions in the past 3 years for diabetic ketoacidosis precipitated by intractable vomiting, and she had been diagnosed with gastroparesis 2 years previously. Assessment of the patient's response to standard treatments for diabetic gastroparesis. These approaches involved tight glycemic control that included subcutaneous insulin infusion via a pump, correction of electrolyte disturbances, use of standard antiemetic and promotility agents, somatostatin-analog treatment, intrapyloric injection of botulinum toxin, and insertion of a percutaneous jejunal feeding tube. Severe diabetic gastroparesis refractory to standard treatments. The neurokinin-receptor antagonist aprepitant was started and her vomiting stopped within 24 h. This treatment was successfully continued for 4 months until a gastric electrical stimulation device was inserted, which enabled aprepitant treatment to be withdrawn and the percutaneous jejunostomy feeding tube to be removed. This successful treatment led to a substantial improvement in the patient's quality of life and overall glycemic control.

The use of novel promotility and prosecretory agents for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation

Chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (C-IBS) are commonly reported gastrointestinal (GI) disorders that have a major impact on health and quality of life. Patients experience a range of symptoms of which infrequency of bowel movement is but one and report that straining, the production of hard stools, and unproductive urges are more bothersome than stool infrequency. Additionally, in C-IBS, patients report abdominal pain and bloating as particularly troubling. Traditional treatments, such as laxatives, are often ineffective, especially in more severe constipation over the long term. In a population-based survey of constipation sufferers, half were not satisfied with their current treatment, due predominantly to poor efficacy. 5-Hydroxytryptamine receptor 4 (5-HT4) agonists stimulate GI motility and intestinal secretion, and tegaserod has demonstrated efficacy in improving bowel habit. Tegaserod also improves constipation-associated symptoms including bloating, abdominal discomfort, stool consistency, and straining in patients with both CIC and C-IBS. However, tegaserod has been withdrawn due to an association with serious adverse cardiovascular effects. Further 5-HT(4) receptor agonists, including prucalopride and TD-5108 are in development and show exciting results in clinical studies in CIC patients, suggesting further product approvals are likely. Headache and diarrhea are the most commonly reported adverse event with this class of agent. Recently a novel prosecretory agent has been approved for the treatment of both CIC and C-IBS. Lubiprostone stimulates chloride secretion through activation of type-2 chloride channels, increasing intestinal secretion and transit, and its use has been associated with improvements in bowel habit and symptoms of constipation. Nausea, diarrhea, and headache are the most commonly reported adverse events. Linaclotide also stimulates intestinal chloride secretion, but this molecule achieves this indirectly, through the activation of guanylate cyclase C. Data are emerging, but the efficacy and safety profile of this agent in the treatment of CIC and C-IBS appears encouraging.

Evaluating the process of care in nonvariceal upper gastrointestinal haemorrhage: a survey of expert vs. non‐expert gastroenterologists

When faced with the same facts, physicians often make different decisions. Aim To perform a survey to measure the process of care and variations in decision-making in nonvariceal upper gastrointestinal tract haemorrhage (NVUGIH) and compare results between experts and non-experts. We administered a vignette survey to elicit knowledge and beliefs about NVUGIH, including 13 'best practice' guidelines. We compared guideline compliance between experts and non-experts. One hundred and eighty-eight gastroenterologists responded (46%). Experts endorsed more 'best practices' than non-experts (93% vs. 85%; P = 0.002). Non-experts were more likely to endorse incorrectly bolus dosing vs. continuous infusion of intravenous proton pump inhibitors (PPIs; 92% vs. 64%; P = 0.005) and to select standard-channel vs. large-channel endoscopes in high-risk bleeding (100% vs. 85%; P = 0.04). There were wide variations within groups regarding the timing of nasogastric lavage, use of promotility agents, use of hemoclips and appropriateness of snaring clots overlying ulcers. Experts are more likely to comply with NVUGIH guidelines. Non-experts diverge from experts in the dosing of PPIs and choice of endoscope in high-risk bleeding. Moreover, there are wide variations in key practices even within groups. This suggests that best practices have been generally well disseminated, but that persistent disconnects exist that should be further investigated.

Frequency scale symptoms for gastroesophageal reflux disease (Frequency Scale for Symptoms of GERD) predicts need for addition of prokinetics to proton pump inhibitor therapy

Frequency scale symptoms for gastroesophageal reflux disease (Frequency Scale for Symptoms of GERD) predicts need for addition of prokinetics to proton pump inhibitor therapy

Gene therapy of Cav1.2 channel with VIP and VIP receptor agonists and antagonists: a novel approach to designing promotility and antimotility agents

Recent findings show that the enteric neurotransmitter VIP enhances gene transcription of the alpha1C subunit of Cav1.2 (L-type) Ca2+ channels in the primary cultures of human colonic circular smooth muscle cells and circular smooth muscle strips. In this study, we investigated whether systemic infusion of VIP in intact animals enhances the gene transcription and protein expression of these channels to accelerate colonic transit. We also investigated whether similar systemic infusions of VPAC1/2 receptor antagonist retards colonic transit by repressing the constitutive gene expression of the alpha1C subunit. We found that the systemic infusion of VIP for 7 days by a surgically implanted osmotic pump enhances the gene and protein expression of the alpha1C subunit and circular muscle contractility in the proximal and the middle rat colons, but not in the distal colon. A similar systemic infusion of VPAC1/2 receptor antagonist represses the expression of the alpha1C subunit and circular smooth muscle contractility in the proximal and the middle colons. The VIP infusion accelerates colonic transit and pellet defecation by rats, whereas the infusion of VPAC1/2 receptor antagonist retards colonic transit and pellet defecation. VPAC1 receptors, but not VPAC2 receptors, mediate the above gene transcription-induced promotility effects of VIP. We conclude that VIP and VPAC(1) receptor agonists may serve as potential promotility agents in constipation-like conditions, whereas VPAC receptor antagonists may serve as potential antimotility agents in diarrhea-like conditions produced by enhanced motility function.

Enhanced Diagnostic Yield with Increased Small Bowel Transit Time During Capsule Endoscopy

Background: The use of promotility agents has been advocated in capsule endoscopy (CE) to increase the rate of intestinal transit time and assure complete visualization over the allotted lifetime of the battery. The effect of small bowel transit time (SBTT) on diagnostic yield, however, has not been evaluated on a large-scale basis. Aim: To assess the effect of SBTT on the ability of CE to detect significant intestinal pathology in a large cohort of patients. Methods: Data were collected prospectively on patients undergoing CE without the use of promotility agents at Johns Hopkins Hospital between January 2006 and June 2007. In patients investigated for anemia or obscure GI bleeding, the following lesions were considered clinically relevant: ulcers, erosions, AVMs, red spots, varices, vascular ectasias, and fresh blood. For those with diarrhea or abdominal pain, only ulcers, erosions, and fresh blood were considered relevant. SBTT was divided into 2-hr intervals between 0-8 hr. Age, gender, indication, inpatient vs. outpatient status, and bowel prep (poor/average/good) were identified as candidate risk factors affecting SBTT. Univariate and bivariate logistic regression analysis was performed to study the effect of SBTT on diagnostic yield. Results: Data were analyzed in 212 patients undergoing CE for 4 different indications (anemia = 42, obscure GI bleeding = 78, diarrhea = 38, pain = 54). Most studies were performed in outpatients (n = 175, 83%); ∼70% of capsules reached the cecum. Mean SBTT overall was 237.0 min (3.9 hr). Age, gender, bowel prep, inpatient status, and study indication did not significantly affect SBTT. Increased SBTT was independently associated with increased diagnostic yield; compared to SBTT = 0-2 hr, patients with SBTT = 2-4 hr (OR = 1.7, p = 0.4), 4-6 hr (OR = 1.8, p = 0.3), and 6-8 hr (OR = 9.6, p = 0.05) were more likely to have a clinically significant finding on CE. In each category of SBTT, >80% patients were reported to have a “good” bowel prep. Conclusion: Prolonged SBTT during CE (>6 hr) is associated with an increased diagnostic yield. This finding does not appear to be related to the quality of the bowel prep, and may be due to a positive effect on image quality during a “slower” study. The use of promotility agents may adversely affect the ability of CE to detect significant intestinal pathology.

Enhanced diagnostic yield with prolonged small bowel transit time during capsule endoscopy.

The effect of small bowel transit time (SBTT) on diagnostic yield during capsule endoscopy (CE) has not been previously evaluated. Our study aim was to assess the effect of SBTT on the likelihood of detecting intestinal pathology during CE. We reviewed collected data on CE studies performed at Johns Hopkins Hospital from January 2006 to June 2007. In patients investigated for anemia or obscure bleeding, the following lesions were considered relevant: ulcers, erosions, AVMs, red spots, varices, vascular ectasias, and presence of blood. In patients with diarrhea or abdominal pain, ulcers, erosions, and blood were considered relevant. Age, gender, study indication, hospital status, and quality of bowel preparation were identified as candidate risk factors affecting SBTT. Univariate logistic and linear regression analyses were performed to study the effect of SBTT on diagnostic yield. Total of 212 CE studies were analyzed; most were in outpatients (n=175, 82.9%) and with excellent bowel preparation (n=177, 83.5%). Mean SBTT was 237.0 min (3.9 hrs). Age, gender, bowel prep, hospital status, and study indication did not significantly affect SBTT. However, increased SBTT was independently associated with increased diagnostic yield; OR=1.7 in SBTT=2-4 hr (p=0.41), OR=1.8 in SBTT=4-6 hrs (p=0.30), OR=9.6 in SBTT=6-8 hrs (p=0.05). Prolonged SBTT during CE (>6 hr) is associated with an increased diagnostic yield. This may be due to a positive effect on image quality during a "slower" study. The use of promotility agents may adversely affect the ability of CE to detect significant intestinal pathology.

Lubiprostone: Easing the Strain of Constipation?

Lubiprostone: Easing the Strain of Constipation?

Gastrointestinal Manifestations of Amyloidosis

Amyloidosis is characterized by extracellular deposition of abnormal protein. There are six types: primary, secondary, hemodialysis-related, hereditary, senile, and localized. Primary (AL) amyloidosis is associated with monoclonal light chains in serum and/or urine with 15% of patients having multiple myeloma. Secondary (AA) amyloidosis is associated with inflammatory, infectious, and neoplastic diseases. The presentation is protean, including macroglossia, a dilated and atonic esophagus, gastric polyps or enlarged folds, and luminal narrowing or ulceration of the colon. Amyloid deposition in the gastrointestinal (GI) tract is greatest in the small intestine. The symptoms include diarrhea, steatorrhea, or constipation. Pseudo-obstruction carries a particularly grave prognosis, often not responding to pro-motility agents. Hepatic involvement is common, but the clinical manifestations are usually mild with hepatomegaly and an elevated alkaline phosphatase level. Biopsies to diagnose amyloidosis can be taken from the fat, kidney, intestine, or bone marrow. The safety of liver biopsies is controversial. With Congo Red stain, amyloid appears red in normal light and apple-green in polarized light. Treatment for AL amyloidosis is chemotherapy and stem cell transplantation; treatment for AA amyloidosis is control of the underlying disease. Amyloidosis should be considered in patients with proteinuria, cardiomyopathy, hepatomegaly (with mildly abnormal liver tests), peripheral and autonomic neuropathy, weight loss, and GI symptoms.

Gastroesophageal reflux disease in pregnancy

Gastroesophageal reflux disease during pregnancy is common. Altered structure and function of the normal physiological barriers to reflux of gastric contents into the oesophagus explain the high incidence of this problem in pregnant women. For the majority of patients, life-style modifications are helpful, but are not sufficient to control symptoms and medication is required. The optimum management of reflux in pregnant patients requires special attention and expertise, since the safety of the mother, foetus and neonate remain the primary focus. Gastroenterologists and obstetricians should work together to optimise treatment. Typically, one utilises a step-up program that starts with life-style modifications and antacids. If those methods fail, histamine-2 receptor antagonists and proton pump inhibitors are tried. Rarely, promotility agents are used. Initiation of these medications must be undertaken after a careful discussion of risks and benefits with patients. In patients without a prior history of reflux, symptoms usually abate after delivery.

Whistler Summary: “The Slow Rate of Rapid Progress”

Whistler Summary: “The Slow Rate of Rapid Progress”

Extreme Variations in Pre-Endoscopic Care of High-Risk Nonvariceal Upper GI Hemorrhage (NVUGIH): Results of a National Vignette Survey of Experts Versus Community Providers

Background: Although EGD is the mainstay of high-risk NVUGIH management, pre-EGD care is critical to optimize outcomes. Yet there is uncertainty about what defines “best practice” in pre-EGD management. Three areas, in particular, have been debated: (1) need for nasogastric lavage (NGL), (2) use of gastric motility agents, and (3) optimal pre-EGD disposition. We conducted a national survey to measure current practice in these 3 areas in a group of experts (Ex) and “non-expert” community providers (NEx). Methods: We developed an online survey that included a vignette of a high-risk NVUGIH patient. Respondents viewed a standardized presentation of a high-risk patient (summary: 42 yo on ASA with melena, epigastric pain, orthostatic BP, no stigmata of liver disease, Hgb = 11), and then received management questions guided by branching conditional logic. Upon EGD, respondents viewed an image of a “spurting” vessel in an ulcer. We measured appropriateness of pre-EGD NGL and motility agents using a standard 9-point RAND Appropriateness Scale (RAS) (1-3 = inappropriate, 4-6 = unsure, 7-9 = appropriate), and calculated the RAND Disagreement Index (DI) for each set of ratings. The DI is a validated measure of provider variation (DI≥1.0 = “extreme variation,” <1.0 = acceptable variation). We surveyed a random sample of 360 GIs from the AGA, and 40 internationally recognized NVUGIH experts. Results: 47% responded (N = 188; 25 experts). Both Ex and NEx groups were generally “unsure” about the appropriateness of NGL (Ex RAS = 5.8; NEx RAS = 5.7; p = 0.8). However, both groups were internally conflicted and polarized, and thus exhibited “extreme variation” regarding NGL (Ex & NEx DI = 4.7). Both groups rated metoclopramide as generally inappropriate (Ex RAS = 3.5, DI = 0.7; NEx RAS = 3.3, DI = 0.8), but rated erythromycin as more appropriate (Ex RAS = 5.4; NEx RAS = 4.1; p = 0.02). However, both groups exhibited extreme variation regarding use of erythromycin (Ex DI = 2.3; NEx DI = 1.6). The most common dispo was transfer to GI suite for immediate EGD (31%), followed by ICU (29%), remain in ER for EGD (15%), monitored floor bed (14%), and non-monitored bed (6%). There was no difference in dispo between Ex and NEx. Conclusions: Both experts and non-experts exhibit extreme variation in their opinion about NGL and promotility agents in the pre-EGD evaluation of high-risk NVUGIH. Although most providers maintain high-risk patients in a monitored environment, there is large variation in the site of monitoring. These variations within and between groups indicate that “best practices” in pre-EGD care remain uncertain and should be subjected to further research and guideline development.