Prokinetic agents are the mainstay of pharmacological treatment in these patients. The main agents that are available for management of diabetic gastropathy are metoclopramide, domperidone, erythromycin and cisapride. These agents differ with respect to mechanism of action, dosing and efficacy, side-effect profile, drug interactions, and current FDA approval status, as noted in TABLE 6.
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Table 6: Prokinetic Agents Used to Treat Symptoms of Gastropathy |
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| Drug | Metoclopramide | Erythromycin | Domperidone | Cisapride |
| Mechanism of Action | Dopamine (D2) receptor antagonist, 5-HT3-receptor antagonist (central and peripheral) | Motilin receptor agonist in the gastrointestinal tract | D2-receptor antagonist (peripheral) | Enhances release of acetylcholine, 5-HT4-receptor |
| Enzyme | Substrate of CYP1A2, 2D6; inhibits CYP2D6 | Substrate of CYP2B6, 3A4; inhibits CYP1A2, 3A4 | Substrate of CYP3A4 | Substrate of 1A2, 2A6, 2B6, 2C8/9, 2C19, 3A4; inhibits CYP2D6 |
| Oral Dosage | 5-20 mg before meals and at bedtime | 125-250 mg four times daily, before meals and at bedtime | 10-20 mg before meals and at bedtime | 5-20 mg before meals and at bedtime |
| Side Effects | Extrapyramidal symptoms, drowsiness, restlessness, diarrhea, weakness | Abdominal pain, cramping, nausea, vomiting, diarrhea, rash, ventricular arrhythmias | Hyperprolactinemia, GI symptoms, rash, muscle cramps, headache | Headache, rash, diarrhea, dyspepsia, flatulence, GI cramping, nausea |
| Drug Interactions | Anticholinergic agents, cyclosporine, digoxin, levodopa, opiate analgesics, succinylcholine | Protease inhibitors, carbamazepine, cyclosporine, triazolam, bromocriptine, digoxin, disopyramide, ergot alkaloids, methylprednisolone, theophylline, cisapride, felodipine, pimozide, warfarin, valproic acid, lovastatin, simvastatin | Anticholinergic agents, MAO inhibitors, H-2 antagonists, proton-pump inhibitors, high-dose antacids | Azole antifungals, nefazodone, maprotiline, protease inhibitors, cimetidine, macrolides, sertindole, phenothiazines, Class Ia and III anti-arrhythmics, tricyclic antidepressants, bepridil, quinolone antibiotics, warfarin |
| FDA Approval | Yes | Yes (not a prokinetic indication) | No (available on compassionate use protocol) | No (available on a limited access protocol) |
Metoclopramide
Metoclopramide accelerates gastric emptying and intestinal transit through a variety of mechanisms peripherally: cholinergic enhancement through cholinesterase inhibition, antagonism of dopaminergic (D2) receptors, and direct effect on the GI smooth muscle. Metoclopramide also acts centrally, in the area postrema, as an antagonist at D2 receptors and 5-HT3 receptors, which may contribute to the anti-emetic action of the drug, and may be vital to the drug’s ability to relieve the symptoms of gastropathy. With metoclopramide therapy, the symptoms of gastropathy appear to improve at different time intervals. Relief of nausea, vomiting, and anorexia may occur within the first three weeks with metoclopramide therapy, than the feelings of persistent postprandial fullness and abdominal pain and distention, which may only resolve with one more week or longer of therapy. The major limiting factor of therapy with metoclopramide is the central nervous system side effects, which include extrapyramidal symptoms.
Erythromycin
Erythromycin increases gastrointestinal motility by binding and stimulating the gastrointestinal peptide motilin. The affinity for the motilin receptor is due to the 14-member macrolide lactone ring that is part of the erythromycin structure. This effect is not related to its antibiotic mechanism of action. In a study by Janssens et al., the effect of erythromycin on gastric emptying in 10 patients with insulin-dependent diabetes mellitus and gastroparesis was studied. The emptying of liquids and solids was studied with intravenous erythromycin versus a placebo. Erythromycin shortened the gastric emptying time of both liquids and solids to normal. Oral erythromycin was also evaluated in studies at doses of 250-500 mg three times a day and four times a day. Though the improvement in gastric emptying rate is not as good as with the intravenous product, the overall improvement in total symptom scores are reported as significant. The major side effect of oral erythromycin therapy is dose-dependent cramps and abdominal pain, which is a major limiting factor to the use of this drug in many patients.
Domperidone
Domperidone is a peripheral D2-receptor antagonist that does not readily enter the blood-brain barrier and therefore exhibits very low incidence of central nervous system side effects. It improves gastrointestinal motility by inhibiting fundic receptive relaxation and enhancing antral contractions. There is also some action on the D2 receptors in the area postrema, leading to anti-emetic activity.
In a study by Silvers et al., 208 patients were enrolled in double-blind fashion to either domperidone or placebo, after a single-blind run in phase. More patients experienced a deterioration of symptoms on the placebo than on domperidone, by both investigator assessment and by patient diary scores (p = 0.025). Of the domperidone-treated patients, 51% had continued symptom improvement compared to 41% of the placebo-treated patients during the double-blind phase (p = 0.038). The associated health-related quality of life (HRQOL) scores for these patients were also evaluated. During the double-blind phase, the domperidone group maintained their high HRQOL scores, while the placebo group showed a significant decline in the physical component summary of the survey (p = 0.05).
The major problem associated with this drug has to do with the fact that domperidone enters the pituitary and prolactin is released, leading to hyperprolactinemia. Currently, the oral dosage of domperidone is not yet approved for use in the United States. It is available through a compassionate use protocol from Janssen Research Foundation, as it awaits FDA approval. The intravenous form of domperidone is no longer available. It was discontinued in the U.S. and worldwide markets due to adverse reports of cardiovascular events.
Cisapride
Cisapride stimulates gastrointestinal motility by facilitating acetylcholine release at the myenteric plexus via stimulation of the 5-HT-4 receptors. It does not penetrate the blood-brain barrier and thus does not exhibit the central nervous system or prolactin related side effects. In a study by Horowitz et al., the effects of cisapride on gastric emptying and gastrointestinal symptoms were studied in 20 insulin-dependent diabetic patients. After four weeks of therapy of either 10 mg four times a day of cisapride or placebo, gastric emptying of solid and liquid was faster in the cisapride group (p < 0.001). Upper gastrointestinal symptoms were also less after cisapride therapy (p < 0.05) versus no change with the placebo (p > 0.2). The major common side effects were abdominal cramping, diarrhea, and headache. Cisapride does not have any anti-emetic property, however it is indicated for gastroesophageal reflux, which is also a symptom of diabetic gastropathy. Overall, cisapride was a viable option for the management of diabetic gastropathy.
However, the manufacturer of cisapride, Janssen Pharmaceutica, stopped marketing cisapride as of July 2000 in the U.S. This decision was based on reports of serious cardiovascular toxicity associated with this drug. The cardiovascular side effects mainly were arrhythmias, including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation. The coadministration of this drug with azole antifungal agents, macrolide antibiotics, anti-HIV protease inhibitors, and some antidepressants were all contraindicated, since these drugs increased cisapride levels due to CYP3A4 drug interactions, leading to increased risk of QT prolongation and subsequent arrhythmias. Currently, the drug is available on an investigational limited access program from the pharmaceutical company. For the patients to receive cisapride, the following criteria must be met: 1) patients must have failed all standard therapeutic modalities; 2) undergo appropriate diagnostic evaluation, including radiologic examination or endoscopy; 3) baseline screening tests must be performed to screen for contraindicated risk factors; 4) the patient must be under the care of a gastroenterologist by consultation, if the prescribing physician is not a gastroenterologist; and 5) institutional review board approval, completion of a Form FDA 1572, and signed informed consent are necessary.
Combination Therapy
Combination therapy with two prokinetic agents is indicated if monotherapy fails. If combination therapy is indicated, it is best to combine drugs with different mechanisms of action. Metoclopramide and erythromycin may currently be the best option for dual therapy, since the other two agents are difficult to obtain. Also, the prokinetic and anti-emetic properties are combination in this dual therapy. Other options for dual therapy are metoclopramide and cisapride, and cisapride and domperidone. The combination of cisapride and erythromycin is contraindicated due to an interaction through CYP3A4 that potentiates cardiovascular side effects.
New Drugs in Research
Several new drugs are being investigated for the management of diabetic gastropathy. An uncontrolled non-randomized study by Koshiyama, et al. evaluated 21 patients with type 2 diabetics on mosapride therapy, a new prokinetic 5-HT4 receptor agonist. Patients were treated for a mean of 100.7 days at 15 mg per day of mosapride, which resulted in the disappearance of gastrointestinal symptoms in all subjects. Another study by Watkins et al. studied the effects of sildenafil on diabetic gastropathy in animal models. The effects of inhibiting the guanosine 3′,5′-cyclic monophosphate- (GMP-) specific phosphodiesterase 5 (PDE5) with sildenafil were tested on gastric emptying. Sildenafil reversed delays in gastric emptying in the diabetic mice, suggesting that increases in cGMP resulting from PDE5 inhibition produce pyloric relaxation and reduce outflow obstruction.
Other agents being studied include tegaserod,a 5-HT4 receptor partial agonist, and botulinum toxin. As further controlled human studies are conducted with these agents, new drugs may become available as treatment options.
Pharmacological Management of Nausea and Vomiting
Nausea and vomiting related to gastropathy can be managed with anti-emetics, in addition to prokinetic therapy. Traditional anti-emetics, such as phenothiazines, and newer, more potent agents, such as the 5-HT3 receptor antagonists (e.g., ondansetron), are available in various modes of administration. Parenteral routes are available for inpatient use, while suppositories are available for outpatient use when oral use is impaired. TABLE 7 lists the various agents that are available for treatment of nausea and vomiting.
| Table 7: Agents Available for the Management of Nausea and Vomiting | |
| Pharmacological Class | Specific Agents |
| Phenothiazines | Chlorpromazine Triflupromazine Perphenazine Prochlorperazine Promethazine Thiethylperazine |
| 5-HT3 Receptor Antagonists | Ondansetron Dolasetron Granisetron |
Nonpharmacological Therapy of Gastropathy
There are very limited options available to patients whose condition does not improve with medical therapy. In patients who lose weight due to the severity of gastropathy, a jejunostomy tube is placed for feedings. Jejunostomy tube feeding has been shown to improve symptoms of gastropathy, glucose control, and gastric emptying rates.
A new technique available for these refractory patients is gastric pacing. In a study by McCallum et al., nine refractory patients were enrolled in a study in which four pairs of cardiac pacing wires were implanted on the serosa of the stomach and electric stimulation was performed for up to one hour before the meal and for up to three hours after the meal. After a mean period of 49 days, gastric emptying significantly improved to the extent that eight of the nine patients did not need to rely on jejunostomy tube feeds. Further studies are necessary to determine the exact role of this technique in the management of these patients. In patients with refractory nausea and vomiting, a study evaluating the effect of Chinese acupuncture has been reported. Acustimulation at P6, a traditional acupuncture point, reduced idiopathic nausea by approximately 40% in patients whose symptoms were refractory to drug therapy. The mechanism of action of this method is unknown, and more studies are required in this area.