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Prokinetic agents for gastroparesis
Introduction
Gastroparesis is a chronic disorder characterized by delayed gastric emptying in the absence of mechanical obstruction . The diagnosis of gastroparesis is confirmed in a symptomatic patient by demonstrating delayed gastric emptying with no organic lesions on upper endoscopy such as ulceration or pyloric stenosis. Gastroparesis can occur in several clinical settings; it is commonly associated with diabetes, post-gastric surgical conditions, and idiopathic (that is, without a known cause). Symptoms of gastroparesis typically include early satiety, postprandial fullness, nausea and vomiting. Delayed gastric emptying in diabetic gastroparesis can interfere with the timing of gastric emptying of food into the small intestine where it is absorbed, leading to erratic glucose control in diabetic patients .
The general principles for treatment of symptomatic gastroparesis are (1) correction of fluid and electrolyte imbalance, (2) correction of nutritional deficiencies, (3) reversal of the cause of gastroparesis, if possible, and most importantly, (4) improvement of symptoms . The treatment options for the patient will vary with the severity of the disease . Dietary modifications are an important aspect for patients: consuming small meals, perhaps more frequent meals to consume enough calories, avoiding food that is high in fat and insoluble fiber and high roughage . In the case of diabetic gastroparesis, good glycemic control is important as hyperglycemia will inhibit upper GI motor function and may limit the effects of prokinetic agents . The next step is with antiemetic agents to control nausea, vomiting and prokinetic agents to improve impaired motility . Recent reviews provide treatment plans based on severity of symptoms, degree of delay of gastric emptying, and ability to maintain hydration and nutrition by oral route .
Gastroparesis as a motility disorder
Symptoms of gastroparesis are expressed in the Gastroparesis Cardinal Symptom Index Daily Dairy which was developed through interviews with patients with gastroparesis . The primary symptoms of gastroparesis include nausea, vomiting, early satiety, postprandial fullness, and upper abdominal pain. Bloating is a commonly expressed symptom and represents, at least in part, postprandial fullness.
Patients with gastroparesis have impaired quality of life, as assessed by the SF-36 . Symptoms that correlate with impaired quality of life include nausea, early satiety, upper abdominal pain, loss of appetite, retching, postprandial fullness, and vomiting.
Using four hour gastric emptying scintigraphy, the symptoms that correlate with gastric retention at 4 hours include early satiety, vomiting, postprandial fullness, and loss of appetite . In a systematic review of studies, defining gastroparesis using optimal 4-hour gastric emptying test methods (either scintigraphy or breath testing), significant associations were found between gastric emptying and nausea, vomiting, abdominal pain, and early satiety/fullness for patients who presented with upper gastrointestinal symptoms . Furthermore, in a recent meta-analysis of published trials, evaluating studies with optimal 4 hour gastric emptying tests, promotility agents were found to accelerate gastric emptying and to produce improvements in upper GI symptoms, with a positive association between improvement in gastric emptying and improvement in upper gastrointestinal symptoms .
Nevertheless, as physicians and patients know, there are a number of patients with symptoms of gastroparesis who have normal gastric emptying, a condition termed Chronic Unexplained Nausea and Vomiting (CUNV) . Perhaps these patients have disordered fundic accommodation or visceral hypersensitivity, pathophysiologic abnormalities initially described in functional dyspepsia.
Gastric prokinetic agents
Gastric prokinetic agents enhance gastric smooth muscle contractility and accelerate gastric emptying. In general, prokinetic agents increase gastric antral contractility, correct gastric dysrhythmias, and improve antroduodenal coordination, areas that may be abnormal in patients with gastroparesis ( Table 24.1 ). Theoretically, treatment of the symptoms of gastroparesis, a condition with delayed gastric emptying, should best be achieved with prokinetic agents which accelerate gastric emptying which should improve symptoms. These agents are prescribed with the intent of both augmenting and coordinating the contractility of gastric smooth muscle and promoting the aboral movement of food to facilitate absorption and maintain nutrition . However, there is a poor correlation of symptoms with gastric emptying, and enhancement of gastric emptying may not necessarily improve symptoms . Not all symptoms of gastroparesis, such as abdominal pain and bloating, may be from delayed gastric emptying. For diabetic gastroparesis, several studies have reported improvement in gastric emptying with prokinetic drugs, but no consistent effects on symptoms or glycemic control . While the relationship between symptoms and gastric emptying is weak, control of gastric emptying is important to regulate delivery of nutrients to the small intestine . Some of the prokinetic agents, metoclopramide and domperidone, also have antiemetic properties due to their central effects. This may explain some of the disparity between prokinetic agents improving gastric emptying and improving symptoms.
Table 24.1
Gastrointestinal dysmotility in gastroparesis.
| Gastric dysmotility |
|
| Colonic transit delay |
At the present time, there is a paucity of prokinetic agents to treat gastroparesis ( Table 24.2 ). Prokinetics presently available for clinical use are metoclopramide and erythromycin. Although each has been shown to improve gastric emptying and decrease symptoms, there are problems with these currently used agents.With metoclopramide, side effects, primarily involving the central nervous system, can occur in up to 20% of patients necessitating stopping this treatment. The prokinetic effects of erythromycin reduce over time due to motilin receptor tachyphylaxis. The serotonin 5-HT 4 receptor agonists, cisapride and tegaserod, increase gastric emptying and were used to treat gastroparesis until they were withdrawn from the market. A new 5-HT-4 agonist, prucalopride, has been approved for chronic constipation, a symptom seen in some patients with gastroparesis.
Table 24.2
Prokinetic agents for gastroparesis: status of availability.
| Class of agent | Available agents | Special circumstances | Under study | Previously studied |
|---|---|---|---|---|
| Dopamine receptor antagonists | Metoclopramide | Domperidone |
|
Itopride |
| Motilin receptor agonists |
|
|
||
| Ghrelin receptor agonists | Relamoralin | |||
|
||||
| 5-HT 4 receptor agonists | Prucalapride |
|
|
|
| Mosapride | Renzapride | |||
| Cholinesterase inhibitors |
|
Acotiamide | ||
| Muscarinic agonists | Bethanechol | |||
| Opiate receptor antagonists | Alvimopan | |||
|
||||
| Pyloric sphincter relaxant | Botulinum toxin |
New prokinetic agents are needed to treat gastroparesis. Receptor and tissue selectivity are important characterizations of new drug development as these influence development of side effects. However, it has been difficult to establish symptomatic benefit with prokinetic drugs in gastroparesis possibly because of the pathophysiological heterogeneity of the patients, the inconsistent relationships between changes in motor function and symptomatic outcomes, potential side effects of medications, and a lack of well-accepted symptom endpoints for clinical trials .
Implementation of prokinetic treatment
When starting a patient on a prokinetic agent, the medications that the patient is taking and other disorders of the patient need to be considered, as these may interfere with the action of the prokinetic agent or increase likelihood of side effects. Opiate narcotic analgesics slow GI transit, particularly gastric emptying and colonic transit. In addition, these agents can themselves cause nausea and vomiting. Medications with anticholinergic activity may delay gastric emptying as well as reduce the effects of prokinetics that work by facilitating acetylcholine release . Drugs with anticholinergic potential that may further decrease gastric emptying should be reduced or stopped. These include particularly the anticholinergic agents used to treat irritable bowel syndrome and spastic urinary bladder.
In patients with diabetic gastroparesis, hyperglycemia can aggrevate symptoms of gastroparesis and reduce the effectiveness of prokinetic agents . Treatment of diabetic gastroparesis should also focus on blood glucose control . Diabetic medications used by the patients can also affect gastric emptying. Of particular concern, is the increased use in the treatment of diabetes of drugs that mimic or modify incretins which slow gastric emptying and may potentially aggravate symptoms of gastroparesis. For example, amylin delays gastric emptying. The amylin analogue, pramlintide, delays gastric emptying in patients with both type 1 and type 2 diabetes . Exenatide is a glucagon-like peptide-1 (GLP-1) mimetic used in T2DM and can delay gastric emptying; although this effect may be less pronounced in patients in whom gastric emptying is already delayed . In contrast, inhibitors of the enzyme dipeptidyl peptidase 4 (DPP-4), which break down GLP-I, do not delay gastric emptying nor reduce food intake . Although these agents can delay gastric emptying, they also improve glucose regulation, which might then improve gastric emptying and symptoms. The benefit of the drugs on glycemic control appears to outweigh the effects on gastric emptying, but these drugs need to be kept in mind when assessing an abnormal gastric emptying study .
Several factors must be considered when choosing a prokinetic drug for the patient with gastroparesis including efficacy, side effects, availability, and cost. Promotility agents including metoclopramide, domperidone, and erythromycin have improved dyspeptic symptoms more effectively than placebo in the majority of studies ; improvement in symptoms with promotility agents has been 40%–45% greater than with placebo . There has been little in the way of controlled investigations directly comparing the different prokinetic medications. A meta-analysis assessing benefits of 4 different drugs in 514 patients in 36 clinical trials reported that the macrolide antibiotic erythromycin was the most potent stimulant of gastric emptying, while the dopamine receptor antagonist domperidone was best at reducing symptoms of gastroparesis . However, as for all metaanalyses, concerns can be raised regarding publication bias in which negative studies are not reported as well as marked differences in study design that can prevent adequate comparisons of the different drugs .
Usually, prokinetic agents are administered 30 minutes before meals to maximize blood levels and gastric prokinetic effects at meal ingestion. In addition, a bedtime dose is often used to help assist indigestible solids emptying from the stomach .
When treating patients with prokinetics, side effects should be monitored. In particular, evidence of depression, anxiety, and movement disorders are monitored in patients being treated with metoclopramide or domperidone. Monitoring for suicidal ideation has been suggested for those treated with 5HT-4 agonists. Electrolytes (K + . Mag 2+ ) and an electrocardiogram are obtained prior to treatment and on followup visit in patients being treated with domperidone. Increasing gastric emptying by a promotility agent can increase peak postprandial glucose levels . Thus, glucose control should be periodically monitored after starting prokinetic agents in diabetic patients.
In gastroparesis, pharmacological therapy with prokinetic agents is often needed on a prolonged basis. Because GI symptoms correlate suboptimally with gastric emptying, the response to treatment is usually judged by an improvement in symptoms; repeating gastric emptying tests is not usually performed. In general patients are treated for 4–6 weeks at the starting dose. In patients with a suboptimal response, the dose of the prokinetic agent can be increased, generally the dose is doubled.
Types of prokinetic agents
Dopamine receptor antagonists
Dopamine is an inhibitor of motor activity of the stomach. Two agents which act as dopamine receptor antagonists, metoclopramide and domperidone, are commonly used in the treatment of patients with gastroparesis . Both agents act to counteract the inhibitory effects of endogenous dopamine on gastric emptying. They further act as antiemetic agents by virtue of their blockade of dopamine receptor- mediated pathways in the brainstem. Domperidone and metoclopramide are equally effective in reducing symptoms of diabetic gastroparesis, particularly nausea and vomiting . However, adverse CNS effects are more severe and more common with metoclopramide, e.g. somnolence and reduction in mental acuity .
Metoclopramide
Metoclopramide (Reglan), a substituted benzamide structurally related to procainamide, has been used since the 1970s to treat gastroparesis . Metoclopramide is a dopamine type 2 receptor antagonist; it also acts as a serotonin 5-HT 4 receptor agonist to stimulate cholinergic neural pathways in the stomach as well as a weak 5-HT 3 receptor antagonist. Metoclopramide has both prokinetic and antiemetic effects. Metoclopramide blocks peripheral dopamine receptors and also releases acetylcholine from intrinsic cholinergic neurons. The prokinetic properties of metoclopramide are limited to the proximal GI tract -increasing gastric fundic and antral contractions and improving antropyloroduodenal coordination. Metoclopramide also has antiemetic effects resulting both from dopamine antagonism in the chemoreceptor zone and from central action at the vomiting center.
Metoclopramide has been approved for short-term use (4–12 weeks) since 1979 for use in diabetic gastroparesis and for prevention of postoperative and chemotherapy-induced nausea and vomiting. In February 2009, the FDA had manufacturers of metoclopramide add a boxed warning to their drug labels about the risk of its long-term or high-dose use. The FDA recommends that treatment should not exceed 3 months. Chronic use of metoclopramide has been linked to tardive dyskinesia, which may include involuntary and repetitive movements of the body.
Controlled trials have shown that metoclopramide may improve symptoms while accelerating gastric emptying of solids and liquids in patients with idiopathic, diabetic, and postvagotomy gastroparesis and in patients with GERD . Metoclopramide has been reported to be effective in the short-term treatment of gastroparesis for up to several weeks . In one 3 week double-blind trial, metoclopramide produced greater symptom improvement and acceleration of gastric emptying than placebo . Individual patient improvements in gastric emptying correlated poorly with reductions in nausea and vomiting emphasizing that symptom benefits may not result from the prokinetic actions of the drug and that antiemetic mechanisms may be important for clinical efficacy . An additional possible mechanism of action of metoclopramide is to normalize gastric slow wave dysrhythmias .
Long-term efficacy for metoclopramide has not been clearly demonstrated; its effect on gastric emptying may diminish during long-term treatment . In diabetic gastroparesis, acute administration of metoclopramide accelerates emptying, but not after 1 month of treatment . However, metoclopramide may continue to relieve symptoms because of its antiemetic effects.
Side effects of long-term use of metoclopramide are of concern and often limit the use of this drug. Side effects of metoclopramide, resulting from its antidopaminergic properties, may occur in up to 30% of patients and are the major factors restricting its use. Most of the side effects of metoclopramide result from its ability to cross the blood brain barrier. Acute dystonic reactions—facial spasm, oculogyric crisis, trismus, and torticollis—occur in 0.2%–2% of patients, often within 24–48 hours of initiating treatment . This side effect, should it occur, is treated with diphenhydramine and stopping metoclopramide. Up to 30% of patients cannot tolerate metoclopramide due either to drowsiness and fatigue or to restlessness and irritability. Depression may occur and may range from mild to severe. Metoclopramide can aggravate underlying depression. Increased prolactin release may result in breast engorgement, lactation, and menstrual irregularity. Prolonged treatment infrequently may produce Parkinsonian-like symptoms, more commonly within the first 6 months after beginning treatment, but occasionally after longer periods . These symptoms usually subside within 2–3 months after discontinuation of metoclopramide. Patients with Parkinson’s disease should not be given metoclopramide. Tardive dyskinesia, characterized by involuntary movement of the face, tongue, or extremities, is an infrequent adverse effect of prolonged use of metoclopramide that may not reverse upon discontinuing the medication. The prevalence of tardive dyskinesia may range from 0.02% to 2% when patients take metoclopramide for at least 3 months . One study reported this as high as 15% . An increase in tardive dyskinesia was reported after cisapride was withdrawn from the market, presumably from patients being switched from cisapride to metoclopramide . Tardive dyskinesia is more common in the elderly, especially older women, and people who have been on the drug for a long time. A recent review on the risk on metoclopramide-induced tardive dyskinesia suggested the risk to be <1% and that this might represent an idiosyncratic response to metoclopramide .
Possible side effects of metoclopramide should be discussed with the patient before starting this medication. Notation of this discussion should be documented in the patient’s medical chart . Some clinicians have patients sign an informed consent to document communicating the risks of metoclopramide. Side effects, particularly movement disorders and depression, should be monitored for during treatment.
The usual starting dose of metoclopramide in adults is 5–10 mg 30 minutes before meals and at bedtime. In patients not responding and without side effects, the dose can be increased to 20 mg. In severe gastroparesis, oral metoclopramide may not be adequately absorbed because of vomiting or delayed gastric emptying; metoclopramide administered intravenously may improve gastric emptying. Liquid metoclopramide may also be of benefit as liquid gastric emptying is often maintained unless severely delayed gastric emptying. An oral disintegrating tablet of metoclopramide has been introduced, which may be of benefit to patients with nausea and vomiting preventing swallowing medications . For individuals with more refractory nausea and vomiting and unable to retain oral medications, subcutaneous injections of metoclopramide have shown symptomatic efficacy in patients . Metoclopramide may also be administered by suppository, or even intraperitoneally in patients undergoing peritoneal dialysis . A nasal spray formulation of metoclopramide has been developed and has undergone clinical trials .
Domperidone
Domperidone (Motilium) is a benzimidazole derivative and is a specific dopamine-2 receptor antagonist. The effects of domperidone in the upper GI tract are similar to those of metoclopramide. Domperidone stimulates upper GI motility by enhancing gastroduodenal contractions and coordination. Domperidone is regarded as a peripheral dopamine receptor type 2 receptor antagonist. It does not readily cross the blood-brain barrier; therefore, it is much less likely to cause extrapyramidal side effects than metoclopramide . However, domperidone also has antiemetic properties by its actions at the chemoreceptor trigger zone on the blood side of the blood-brain barrier .
Domperidone has been studied primarily in diabetic gastroparesis. It increases both solid and liquid emptying, especially in those patients with a severe delay in gastric emptying . Symptomatic improvement may not correlate with improvement in emptying as improvement of nausea and vomiting may also result from antiemetic effects. Symptomatic benefit of domperidone can also occur in diabetic patients with normal gastric emptying . In a small study of 6 patients with diabetic gastroparesis, symptom improvement on domperidone was associated with resolution of gastric slow wave dysrhythmias suggestive of a possible gastric antiarrhythmic effect of this agent .
In a phase III trial of diabetics with symptoms suggestive of gastroparesis, 269 patients initially received domperidone 20 mg four times a day for four weeks . 77 percent of patients responded to therapy, defined as more than 30% reduction in symptoms. Responders were then randomized to double-blind continuation of domperidone versus withdrawal to placebo. Those switched to placebo had worsening of overall symptoms compared to the patients maintained on domperidone. The main symptom that had most deterioration on placebo was early satiety with trends for worsening of nausea, bloating, and vomiting.
The effect of long-term treatment with domperidone has been variable. At 6 weeks, the effect of domperidone on solid phase gastric emptying was lost, whereas the improvement of liquid gastric emptying was maintained . Another study found that nausea and vomiting were improved compared with baseline values after 6 weeks of treatment, but there was no change in solid phase gastric emptying . Other studies have suggested that improvement in gastric emptying and symptoms was still present after 1 year of treatment .
Domperidone is often used in patients whom have had side effects to metoclopramide or in those who are concerned about the possibility of developing side effects with metoclopramide. Domperidone is especially useful in gastroparetic patients with Parkinson’s disease in whom it can improve gastric emptying without blocking the central dopaminergic actions of treatment for Parkinson’s disease . Domperidone would work peripherally for GI dysmotility and symptoms; l -dopa would still work centrally for the Parkinsonian symptoms.
In the United States, domperidone is not approved by the Food and Drug Administration (FDA) and cannot be obtained by routine prescription and is not covered by health care plans. Traditionally, domperidone has been obtainable from other countries, from Internet websites, or from compounding pharmacies within the US. These practices have been discouraged by the FDA. Physicans who would like to use domperidone for their patients can submit an Investigative New Drug (IND) application to the FDA and their IRB to use this medication. Using this mechanism, patients sign an informed consent document and purchase domperidone from an FDA-approved pharmacy ($70 per month for 10 mg po TID). The FDA protocol entails obtaining an electrocardiogram and electrolytes including magnesium prior to initiation of treatment and repeating these on treatment with domperidone.
Domperidone is generally started at 10 mg three times a day. If symptoms persist after 4–8 weeks, the dose is increased to 20 mg three to four times daily. A trial of up to 80 mg/day for up to a month is considered the time needed to assess its efficacy .
Because it does not cross the blood-brain barrier, domperidone has a more favorable side effect profile compared to metoclopramide . The main side effects of domperidone are cardiac arrhythmias, breast lactation, headaches, and diarrhea. The side effects of domperidone can be secondary to increased prolactin levels, and include breast engorgement and galactorrhea. In addition, the high prolactin levels interfere with FSH and LH, which leads to amenorrhea in some patients. Generally, however, one does not monitor prolactin levels before or during treatment with domperidone. CNS side effects are minimal. Dystonias and other movement disorders are uncommon with this agent. Cardiac effects including QTc prolongation and cardiac arrhythmias are the main concerns when it comes to the use of domperidone in Gp [80–82]. Symptoms of the cardiac arrhythmias can be chest pain, light headedness, and/ordizziness. For this reason, the use in Europe several years ago was discouraged. In US, the FDA suggests careful following of the EKG QTc interval and potassium and magnesium levels. An intravenous form of domperidone was withdrawn in the 1980s due to rare reports of fatal cardiac arrhythmias.
In a large prospective cohort study, 115 patients (88 idiopathic Gp, 16 diabetic Gp, and 9 postsurgical Gp) showed significant improvement in Gp symptoms including nausea, vomiting, retching, early satiety and upper abdominal pain, 44 patients reported having side effects, the most common were palpitations, diarrhea and headache . A recent study of 34 patients taking domperidone at 10 mg TID showed an improvement in gastroparesis symptoms, particularly nausea and early satiety (P<0.05) . Domperidone at the conventionally used doses to treat gastroparesis (30–80 mg/d) was associated with QTc prolongation in only 6% of patients with no QT interval reaching the point considered to be clinically significant . These data suggest that with careful monitoring, domperidone can be safely prescribed at doses of 30–80 mg daily for the treatment of gastroparesis.
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