Domperidone

Domperidone is a synthetic benzimidazole compound that is used as a prokinetic agent for treatment of upper gastrointestinal (GI) motility disorders and as an antiemetic. This compound also is gaining popularity as a galactagogue. Domperidone is a specific dopaminei receptor (D2) antagonist that does not cross the blood-brain barrier. It exerts its effect at peripheral D2 receptors in the GI tract; the chemoreceptor trigger zone (CRT), which is outside the blood-brain barrier; and the pituitary.1-4 The basic pharmacology of domperidone and its use as a galactagogue have been reviewed in this journal and elsewhere.5 7 This article provides background information for use of domperidone as an antiemetic, with a focus on Parkinson's disease, and as a prokinetic agent, with a focus on diabetic gastropathy.

Domperidone as An Antiemetic

Background

Vomiting is an organized process that is coordinated by an area of the medulla called the vomiting center or central pattern generator. The vomiting center receives input from several sources, including the CRT, GI tract (stomach and small intestine), higher cortical centers of the brain and the labyrinths, and orchestrates the gastromotor functions that result in vomiting. Domperidone's action as an antiemetic is thought to stem from antagonism of D2 receotors at the CRT.1,3,8,9

Parkinson's Disease

Parkinson's disease is a progressive movement disorder characterized by degeneration of dopaminergic neurones in the substantia nigra of the midbrain. Treatment is aimed at increasing dopaminergic stimulation of the striatal neurons involved in controlling movement, using dopamine-increasing agents or dopamine agonists.'" Concomitant stimulation of dopamine receptors at the CRT and, possibly, in the GI tract results in the common side effects of nausea and vomiting. Domperidone is used prophylactically to counteract these effects.11-12

Levodopa (L-Dopa), a precursor of dopamine, is a mainstay in the treatment of Parkinson's disease. Oral domperidone (10 to 20 mg 3 times a day) has been shown to reduce levodopa-induced nausea and vomiting.13

Domperidone (60 mg daily) reduced the incidence of nausea and vomiting in a placebo-controlled study of patients receiving bromocriptine (a dopamine receptor agonist) therapy and allowed higher doses of bromocriptine to be tolerated.14

Parkinson's disease is characterized by unpredictable "off periods of poor drug response and increased parkinsonian symptomatology. Management of off periods with apomorphine (intermittent injections or continuous infusion), a short-acting dopamine receptor agonist, was made practical by the use of domperidone to counteract apomorphine's potent emetic effects. Domperidone pretreatment (10 to 20 mg by mouth 3 times a day) is typically started 1 to 3 days before apomorphine treatment is begun. Patients can often gradually reduce or stop domperidone after a few weeks, as tolerance develops to apomorphine's emetic effects, possibly due to down regulation of dopamine receptor sensitivity in the medulla (vomiting center) after continuous dopaminergic stimulation.IM"

Domperidone (20 mg 3 times a day) has been used to allow quicker titration of pergolide as an adjunct to L-Dopa therapy.20 Hobson et al:l suggest domperidone as an adjunct to ropinirol or pramipexole therapy, two newer dopamine agonists that are relatively specific for D2 receptors.

Surgery-Postsurgical, Chemotherapy- or Radiation-Induced Emesis

Early studies of domperidone's utility for postsurgical, and chemotherapy- or radiation-induced emesis used intravenous (IV) or intramuscular administration (reviewed elsewhere).4However, parenteral forms of domperidone were withdrawn worldwide following reports of severe adverse cardiac effects.l: Oral domperidone has seen limited use in treatment and prevention of postoperative nausea.22 In general, serotonin receptor antagonists are now recommended as first-line treatment of chemotherapy- or radiation-induced emesis; dopamine receptor antagonists may have a place as alternative or adjunct therapy.8,23-25

Prokinetic Activity of Domperidone

The stomach's function of receiving, preparing and delivering nutrients to the small intestine in a usable form is a complex process in which the central, autonomie and enteric nervous systems all play a role. Briefly, the main anatomical parts of the stomach are the cardia, fundus, body and antrum. At the beginning of a meal, the fundus relaxes to make room tor the incoming food. After a lag phase, regular contractions of the antrum mix food particles with acid and pepsin into a suspension called chyme, which is then emptied through the pyloric sphincter into the duodenum, the first part of the small intestine. The gastric emptying rate depends upon the physical and chemical characteristics of the stomach's contents; typical gastric emptying time is 1 to 4 hours. In the interdigestive period, four phases of spontaneous gastric contractions, some of which are controlled by pacemaker cells of the stomach (interstitial cells of Cajal), clear the stomach of undigestible solids.26

Dopamine is synthesized in the GI tract, spleen and pancreas in humans; Dl-like and D2-like receptors have been demonstrated in several mammals at various GI sites. Dopamine's effect on the GI tract is primarily inhibitory, as evidenced by reduced lower esophageal sphincter tone, reduced gastric tone and intragastric pressure, and decreased antroduodenal coordination.1,3,26-28

Dopamine appears to directly inhibit gastric muscle contractions via postjunctional muscular D2 receptors in the lower esophageal sphincter, fundus and antrum.1,3,27 Domperidone's prokinetic effect is likely a result of blockade of D2 inhibitory receptors. It has been shown to increase lower esophageal sphincter pressure, improve antroduodenal coordination and gastric emptying and normalize gastric dysrhythmias.28-32

Dopamine also has an indirect inhibitory effect via inhibition of cholinergic transmission in the myenteric plexus, which regulates the circular and longitudinal layers of smooth muscle. This inhibition was shown in isolated guinea pig stomach to be sensitive to domperidone, indicating mediation by prejunctional D2 receptors on postganglionic cholinergic neurons." w However, domperidone has not been shown to have procholinergic activity in isolated human stomach.1-3,35

Diabetic Gastropathy

Diabetic gastropathy is an umbrella term for a constellation of upper GI symptoms in patients with diabetes, including nausea, vomiting, bloating, abdominal discomfort and early satiety or fullness, suggestive of underlying neuromuscular dysfunctions of the GI tract. Potential neuromuscular dysfunctions include gastroparesis (delayed gastric emptying), gastric dysrhythmias, antralhypomotility and dilation, reduced antroduodenal coordination and gastric tone dysfunction26,36-37

The correlation between upper GI symptoms and the rate of gastric emptying is relatively weak, thus gastroparesis is considered to be an indicator of gastroduodenal motor abnormality, rather than the sole cause of the symptoms.3,26,29,36 Upper GI symptoms may affect up to 50% of patients with diabetes, but symptoms do not necessarily predict delayed gastric emptying.3,26,37 Conversely, patients with diabetes who have poor gastric emptying (up to 50% of patients with type 1 diabetes) may have no upper GI symptoms, although they may experience poor glycemie control due to mismatch of insulin administration with emptying of nutrients into the small bowel.3,26,36,37

The etiology of diabetic gastropathy is not well understood. Autonomie neuropathy and hyperglycemia are thought to be two dominant factors.

Autonomie Neuropathy

Yagal nerve impairment might alter antroduodenal inotility, gastroesophageal reflux activity and gastric secretory function. Although the association between gastroparesis and abnormal autonomie function is relatively weak, it is thought to be a contributing factor.26,36-37

Hyperglycemia/Glucose Toxicity

An inverse relationship has been shown between gastric emptying and blood-glucose concentration both in healthy individuals and in those with type 1 or type 2 diabetes. In addition, acute changes in blood-glucose concentration can alter the perception of sensations from the stomach and duodenum.26,36-37

Other Factors

Knteric neuropathy, altered postprandial release of hormones and neurotransmitters, visceral hypersensitivity and psychological disorders may potentially contribute to gastric dysfunction in patients with diabetes. In addition, there are many other causes of gastroparesis besides diabetes.26,36-37

Evaluation of Patients

Evaluation of patients with diabetes who present with upper GI symptoms should include a complete physical examination and medical history. Other causes of upper GI symptoms and poor gastric emptying, such as mechanical obstruction, poor glucose control or medications that slow gastric emptying, eg, anticholinergics and dopaminergics, should be ruled out.26,36-37 Gastric scintigraphy (direct measure of the transit time of a radiolabeled meal) is the most common, and considered to be the most accurate, way to evaluate gastric emptying.36 Other methods for evaluating gastric myoelectrical events include electrogastrophy, scintigraphic breath tests, ultrasonography, magnetic resonance imaging and antroduodenal manometry.37

Treatment

Treatment focuses on improving upper GI symptoms, improving glycemie control and optimizing nutritional intake and quality of life. Optimizing glucose control and avoiding drugs that can slow gastric emptying, followed by dietary and lifestyle modifications, are the usual initial course of treatment. Common recommendations include smaller, more frequent meals that are low in fat and fiber (to avoid bezoar formation); and increased nutrient liquids, although controlled trials have not proven this approach to be effective. Moderate exercise is encouraged, as this accelerates gastric emptying.-26,36-37

Prokinetic agents are the mainstay of pharmacological treatment. Mechanisms of action include dopamine D2 receptor blockade (domperidone and metoclopramide), stimulation of 5HT4 receptors (metoclopramide and cisapride) and stimulation of motilin receptors (erythromycin).36 Placement of a feeding jejunostomy tube is a treatment of last resort.26,36-37

Efficacy

Numerous clinical trials have consistently shown oral domperidone, typically 20 mg 4 times a day, to improve symptom scores, improve gastric emptying, correct gastric dysrhythmias, decrease hospitalizations and improve the quality of life in patients with diabetic gastropathy or gastroparesis.2-3,26,29-30,38-44 The complex etiology of diabetic gastropathy, and the weak association between more objective measurements of gastroduodenal function (gastric emptying, electrogastrographic measurements) and symptoms, complicate interpretation of these studies. Domperidone's antiemetic function must also be considered in assessing symptom improvement.

Symptomatic improvement is the most common outcome evaluated in clinical trials of domperidone efficacy. Other parameters include measurement of gastric emptying, gastric myoelectrical rhythm recording, health-related quality of life assessment and hospitalization rates. Many studies have methodological limitations related to one or more parameters: small study size, lack of reporting of patients' blood glucose levels, lack of placebo control, lack of randomization, unblinded treatment or nonvalidated measurement of symptoms.29,36,38-39 A meta-analysis39 of clinical studies of four prokinetics (cisapride, metoclopramide, domperidone and erythromycin) showed that open-trial and single-blind studies showed greater improvement in both symptom assessment and gastric emptying times than did double-blind trials, indicating a substantial placebo effect and/or bias. The use of domperidone and metoclopramide in the treatment of gastroparesis is currently under review by the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group.4'

The largest clinical trial4042 used a two-phase withdrawal design to enrich the trial with treatment responders. In phase I, 269 insulin-dependent patients with diabetes who had symptoms of gastroparesis [≥8 out of 15 maximum in total symptom score (TSS)] received single-blind treatment with domperidone 20 mg 4 times a day for 4 weeks. Patients were classified as responders (n = 208, 77%) if they showed statistically significant improvement in TSS at the end of phase T (mean change from baseline 6.52; P

Health-related quality of life (HRQOL) was evaluated using the Medical Outcomes Study Short-Form 36 (SF-36), with aggregation into a physical component summary (PCS) or mental component summary (MCS) index; higher scores indicate better HRQOL. Responders also experienced significant improvement from baseline in both PCS (+3.47; P

Patients classified as responders in phase I were randomized for phase II, a double-blind parallel-group 4-week withdrawal study with either placebo (n = 103) or domperidone 20 mg 4 times a day (n = 105). During phase II, both groups experienced deterioration in TSS. The placebo group experienced significantly greater deterioration than the domperidone group (+1.84 placebo versus +0.85 domperidone; between-group difference P = 0.025).41

In phase II, responders receiving placebo demonstrated a significant decline in PCS (1.77; P- 0.20), while those receiving domperidone experienced a statistically insignificant change (+0.65; P = 0.361; between-group P = 0.050). Both groups' MCS scores were statistically unchanged in phase II.40

Patients were also evaluated by scintigraphy at the outset of the study for gastric emptying rates and classified into delayed gastric emptying (DGE; n - 126; 44%) and normal gastric emptying (NGE) classes; criteria were not reported. No significant difference was seen between NGE and DGE groups in baseline TSS or TSS improvement during phase I, nor in the deterioration of TSS in phase II.41-42

Talley38 has suggested that the two-phase withdrawal design might be suboptimal because of the open-trial design of the first phase. In addition, a straightforward interpretation of the results of the withdrawal phase depends on the assumption that the disease relapses and remits, which may not be the pattern in diabetic gastroparesis. Silvers et al41 acknowledge that potential bias of investigators in assigning total symptom scores at the end of phase I might have been a factor in the deterioration of TSS by the domperidone group in phase II. Talley38 suggests that double-blind, parallel group studies remain the trial design of choice, using validated outcome measures of both symptoms and quality of life.

Gl Symptoms in Parkinson's

Patients with Parkinson's disease can experience upper GI symptoms as a result of cerebral degeneration, degeneration of the myenteric plexus and antiparkinsonian medication.*' Extended domperidone therapy (20 mg 4 times a day, mean follow-up 3 years) has been shown to improve upper GI symptoms and gastric emptying."'47

Gastroesophageal Reflux Disease

Domperidone has not been shown conclusively to reduce the number of reflux episodes or improve gastroesophageal reflux dis ease (GERD) symptoms. At this time, acid-suppressive agents have become the drugs of choice for GERD.48

Tolerability/Adverse Effects

In one study of 17 patients with documented gastroparesis, oral domperidone 40 to 120 mg/day was used for periods of up to 4 years and was well tolerated.4'4 In the large study by Silvers et al,41 the tolerability profile was similar to placebo. The most common (occurring in as many as 10% to 20% of patients) adverse effects described in most studies are related to increased prolactin levels due to antagonism of D2 receptors in the anterior pituitary, including gynecomastia, galactorrhea, breast tenderness or menstrual irregularities.14- In a double-blind, nonplacebo-controlled, comparison of domperidone and metoclopramide in 93 insulin-dependent patients with diabetes, elicited C]NS effects (somnolence, akathisia, asthenia, anxiety, depression and mental acuity) were fewer and less severe for domperidone.49 case reports describing extrapyramidal symptoms have been summarized elsewhere' and in general indicate that the risk of developing extrapyramidal side effects is minimal when domperidone is taken orally by adults at recommended doses.

Increased blood pressure and heart rate have been seen in patients treated with oral domperidone 10 mg 3 times a day in conjunction with continuous subcutaneous infusion of apomorphine.'" Parenteral forms of the drug were withdrawn from the market in 1984 due to QT prolongation, ventricular arrhythmia and cardiac arrest in patients receiving high IV doses.3,12 Physiologically relevant concentrations of domperidone have been shown to prolong cardiac repolarization in isolated guinea pighearts, indicating the potential for association with QT prolongation and ventricular arrhythmia clinically." No clinically important changes in vital signs or electrocardiographic activity were observed in 286 patients using domperidone 20 mg 4 times a day for 4 weeks and in 105 patients who were treated for 8 weeks.41

Summary

Domperidone is a dopamine D2 receptor antagonist with antiemetic properties and localization outside the blood-brain barrier that have made it a useful adjunct in therapy for Parkinson's disease. There has been a renewed interest in antidopaminergic prokinetic agents since the withdrawal of cisapride, a 5-HT4 agonist, from the market.1 Domperidone continues to be an attractive alternative to metoclopramide because it causes fewer CNS side effects. Patients receiving domperidone or other prokinetic agents for diabetic gastropathy or gastroparesis should also be managing diet, lifestyle and other medications to optimize gastric motility.

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Lisa M. Albright, PhD

Austin, Texas

Address coirespondence to: Lisa M. Albright, PhD, at lmalbr-@alum.mit.edu

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