Metoclopramide, Domperidone, Cisapride... How to treat diabetic gastroparesis?

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Introduction: Abdominal distension, nausea, gastric emptying is obviously delayed, and the symptoms gradually worsen.
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How to treat diabetic gastroparesis? Diabetes and gastroparesis Diabetic gastroparesis (DGp) is one of many diabetic autonomic neuropathies, which is common clinically, but the diagnosis is often not timely
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It is estimated that DGp affects 20%-50% of people with diabetes, especially those with type 1 diabetes and long-term (≥10 years) type 2 diabetes
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The average age of onset of DGp is ​​about 34 years old, and the prevalence is positively correlated with age.
Type 1 diabetes is more common than type 2 diabetes
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 Table 1 Diabetic autonomic neuropathy Common symptoms of diabetic gastroparesis The common signs and symptoms of DGp are shown in Table 2
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According to reports, among 146 patients with gastroparesis, 92% had nausea, 84% had vomiting, 75% had abdominal distension, and 60% had early satiety, most often with "delayed gastric emptying"
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Compared with patients with type 2 diabetes, patients with type 1 diabetes exhibit more severe symptoms, be hospitalized more frequently, and have a lower rate of symptom relief
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Table 2 Common symptoms of diabetic gastroparesis The "general principle" of the treatment of diabetic gastroparesis The goal of treatment is to reduce the burden of symptoms, ensure adequate nutritional intake, and improve the quality of life score
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Some literature recommends "step-by-step treatment" (Figure 1).
The general principle is to adopt safe and less invasive interventions as much as possible in the initial stage, and reserve more invasive options (such as surgery) for patients whose initial treatment fails
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Figure 1 Step-by-step treatment of gastroparesis 1.
Blood sugar control The severity of diabetic neuropathy is positively correlated with the duration of hyperglycemia and blood sugar level, so improving blood sugar control is of great significance
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The symptoms of gastroparesis (such as nausea, vomiting, and unstable energy intake) increase the difficulty of balancing carbohydrate intake while avoiding hypoglycemia
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Therefore, doctors should pay more attention to the selection and dosage adjustment of hypoglycemic drugs
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 It should be emphasized that GLP-1RA hypoglycemic drugs can delay gastrointestinal motility and induce upper gastrointestinal symptoms.
Therefore, it is necessary to consider whether to stop using them in DGp patients
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 2.
Diet adjustments to maintain nutritional balance, quit smoking and alcohol
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Patients with nausea, early satiety, abdominal distension and loss of appetite should eat small and frequent meals (4 to 5 times a day) and eat easily digestible foods
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 Recommend low-fat, low-fiber, small particle or liquid diet, start with restricting intake of "difficult food" in the initial stage, and gradually tighten it (the basic principle is that solids need to be ground into particles ≤ 2 mm in diameter in order to be removed from the stomach as soon as possible Emptying, otherwise the lipids in the small intestine will stimulate the gastrointestinal feedback mechanism and cause delayed gastric emptying)
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Avoid fried foods and non-digestible solid foods.
Eat fiber-rich foods, such as buckwheat, corn, fresh vegetable kelp, seaweed, etc.
, to facilitate gastrointestinal peristalsis and maintain smooth stool
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 3.
Rehydration and nutrition.
Patients with repeated vomiting and reduced oral intake may cause hypokalemia, metabolic alkalosis and dehydration.
In addition, micronutrients and vitamin deficiencies may occur
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For patients with mild gastroparesis, rehydration and vitamin supplementation should be given orally
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For patients who cannot tolerate solid foods, supplements and vitamins can be added to a liquid diet or a homogenized diet
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Patients with refractory symptoms may require enteral or parenteral nutrition supplements
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Drug therapy—accelerating "gastric emptying" It is common for diabetic patients to use drugs or even multiple drugs (≥5 types).
Some drugs may cause delayed gastric emptying due to drug-induced gastric emptying (Table 3) and should be carefully evaluated Disable
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 Specific to drugs that accelerate gastric emptying, metoclopramide and erythromycin are drugs approved by the FDA to accelerate gastric emptying
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However, although these drugs can improve symptoms and promote nutrient intake, they also bring side effects that cannot be ignored (described in detail below)
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In terms of dosage form, suspension formulations are more stable than tablets
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 Table 3 Drugs/factors affecting gastric emptying 1.
Metoclopramide is the first-line drug for gastroparesis, metoclopramide reduces vomiting through central and peripheral effects (central effect is attributed to dopamine receptor antagonism, peripheral The effect is attributed to cholinergic stimulation and increased foregut motility), and administration methods include oral (tablets, liquid preparations), parenteral, rectal or nasal feeding
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The recommended treatment time should not exceed 12 weeks, unless the patient's treatment benefits outweigh the risks
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Liquid preparations are preferred, starting at a small dose of 5 mg, taken 15 minutes before meals or before going to bed, and the maximum tolerated dose is 40 mg/d, taken in divided doses; drug holidays can also be used (referring to a 2-week period between two prescriptions) Drug-free period) or treatment methods that reduce the frequency of administration (such as 5 mg divided into 2 doses before the main meal during the day)
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For patients who cannot be taken orally, it can also be administered intravenously, intramuscularly or subcutaneously
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Medication safety is limited by the side effects of metoclopramide-in one study, more than one-third of patients reported acute adverse reactions in the trial
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This is because metoclopramide can cross the blood-brain barrier, increasing the risk of hyperprolactinemia and extrapyramidal side effects
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Specifically: ➤Hyperprolactinemia is associated with the risk of galactorrhea, amenorrhea, gynecomastia and impotence; ➤The most common extrapyramidal side effect is acute reversible dystonia, which is most common in young women; ➤Methoxy The risk of chlorpramide-related Parkinson's syndrome increases within 3 months after starting the medication, and usually subsides within a few months after stopping the medication; ➤Drug-related tardive dyskinesia is a potentially irreversible dyskinesia.
(It is more likely to occur in elderly women and patients exposed to higher cumulative doses of metoclopramide)
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Therefore, the US FDA approved metoclopramide for "alleviating the symptoms of adults with acute and recurrent diabetic gastroparesis", accompanied by a black box warning about "tardive dyskinesia"
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2.
Domperidone For patients whose metoclopramide treatment cannot relieve symptoms or have side effects, domperidone can be considered
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The degree of symptom improvement is similar to that of metoclopramide
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It is recommended to start with a small dose, 10mg once, 3 times a day; if the symptoms persist, increase to 20mg once, 3 times a day, and add another 1 time before going to bed
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  Medication Safety Unlike metoclopramide, it does not cross the blood-brain barrier, so the risk of extrapyramidal side effects is extremely low, but it also brings some side effects
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➤Domperidone increases serum prolactin levels and can cause gynecomastia
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➤Although domperidone is used in a dose of 20 mg, 4 times a day, the effect on the QT interval of healthy people seems to be negligible, but concerns about the cardiac effects of this drug have prompted the European Medicines Agency to recommend limiting the use of this drug In the "short-term treatment of nausea and vomiting", the daily dose is limited to <30mg; ➤For moderate or severe liver function impairment or increased risk of cardiac events (such as prolonged QTc interval, severe ventricular arrhythmia, torsades de pointes) Patients with tachycardia or sudden cardiac death) should be cautious; ➤ In addition, except for apomorphine, domperidone and other QT prolonging drugs are forbidden to be used in combination
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In the United States, the indication for diabetic gastroparesis of domperidone has not been approved by the FDA, but it is mentioned in another plan issued by the FDA that the administration of related drugs requires electrolyte and electrocardiogram monitoring before and during treatment
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3.
Serotonin receptor agonist (cisapride) Cisapride is a 5-HT4 agonist that can stimulate gastric antrum and duodenal movement, and accelerate the emptying of solids and liquids from the stomach (due to fear of occurrence Unexpected cardiac event, the drug has been withdrawn from the US market)
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Generally, for patients who try all other prokinetic treatments that are ineffective, lowering the dose can relieve other side effects of cisapride (including abdominal discomfort and diarrhea)
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The recommended dosage for use is 10~20mg once, 4 times a day, half an hour before each meal and before going to bed, the dose should not exceed 1mg/kg/d or 60~80mg/d, (because the heart rhythm is observed when the high dose is given Abnormality)
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 Other: Currently, other 5-HT4 agonists are being developed to treat gastroparesis
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In a blinded crossover study, prucalopride, previously used to treat constipation, improved the incidence and symptoms of gastric emptying in patients with gastroparesis
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However, 4 of the 28 patients in the study discontinued the drug due to adverse reactions
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Another new drug under development-Velusetrag accelerates gastrointestinal motility in patients with diabetic gastroparesis, and is currently waiting for the results of gastroparesis related research
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 4.
Motilin receptor agonists (erythromycin and azithromycin).
Motilin is a peptide hormone composed of 22 amino acids and is expressed throughout the intestinal tract
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Erythromycin: Erythromycin is a macrolide antibiotic.
It is an oral (tablet and suspension) and intravenous preparation.
It can be used as a motilin receptor agonist, and can be used as The dose used for antibacterial action" stimulates gastric migrating compound movement
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For patients who try to use metoclopramide and domperidone to treat patients who do not respond, oral erythromycin should be treated
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Recommendations for use ➤Low-dose intravenous injection of erythromycin (40mg) can induce early gastric migrating compound movement; ➤higher dose (200mg) can induce substantial contraction of the gastric antrum, but will not affect the small intestine and accelerate gastric emptying; ➤venous Administration is better than oral administration on gastric emptying, but intravenous administration of more than 250mg will not further increase the efficacy; ➤High blood sugar levels and repeated administration (3-4 weeks), gastric discharge caused by erythromycin Air acceleration is weakened
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Azithromycin: Limited evidence suggests that azithromycin, the second macrolide antibiotic, may also improve gastric emptying.
Compared to erythromycin, azithromycin has a longer half-life, fewer drug interactions, and fewer side effects
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However, similar to erythromycin, the use of azithromycin is associated with an increased risk of sudden cardiac death, especially in patients who have a potential risk of heart disease
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 5.
Ghrelin antagonist Ghrelin is a natural ligand for growth hormone secretion-stimulating receptors and is expressed throughout the gastrointestinal tract
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In drug dosages, ghrelin can promote gastric motility in healthy people and patients with idiopathic gastroparesis
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 Two ghrelin receptor agonists (ie TZP-102, relamorelin) have been evaluated for diabetic gastroparesis: ➤TZP-102's Phase 2b trial in diabetic gastroparesis patients was terminated early due to ineffective drugs ➤There are two large phase 2 studies showing that subcutaneous injection of ghrelin receptor agonist relamorin (RM-131) can treat diabetic gastroparesis
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However, although the incidence of adverse reactions of relamorelin is similar to that of placebo, 15% of diabetic patients receiving relamorelin have worsening of blood sugar
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Five patients were hospitalized due to complications of hyperglycemia, and three of them developed diabetic ketoacidosis
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 Drug therapy-management of "nausea and abdominal pain" Although abdominal pain is a common symptom of diabetic gastroparesis, there is a lack of research to explore the best way to deal with this symptom
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 1.
Antiemetics ➤ Antiemetics: such as phenothiazines (such as prochlorperazine), antihistamines (such as promethazine or meclizine), transdermal administration of scopolamine and serotonin receptors Antagonists (such as ondansetron) can be used to treat nausea caused by gastroparesis
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However, the efficacy of these drugs has not been evaluated in RCT
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 ➤Apreprient under development: A placebo-controlled study of apreprient, a neurokinin-1 receptor antagonist, reported mixed results in patients with nausea and vomiting with or without gastroparesis
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The drug has been approved by the FDA for the management of chemotherapy-related nausea and vomiting
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 2.
Tricyclic antidepressants ➤Amitriptyline: It is beneficial to treat neuropathic pain and improve symptoms related to functional gastrointestinal diseases
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However, amitriptyline has anticholinergic effects and may delay gastric emptying
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➤Nortriptyline: It is not superior to placebo in patients with idiopathic gastroparesis
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 3.
Other neuromodulators ➤Pregabalin or gabapentin: It can be considered, but there is no evidence to support it
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➤Opiates: Many patients will eventually need to use opioids to treat abdominal pain associated with gastroparesis
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 It needs to be emphasized that opioids can delay the transit of the small intestine and colon, and are associated with narcotic bowel syndrome, and are dependent, addictive, and may cause hyperalgesia.
It is strongly recommended not to use them if necessary
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References: [1]Adil E.
Bharucha, Yogish C.
Kudva, David O.
Prichard.
Diabetic Gastroparesis[J].
Endocrine Reviews.
2019.
[2]The Chinese Medical Association Diabetes Branch Neurological Complications Group.
Diabetic Neuropathy Expert consensus on diagnosis and treatment (2021 edition)[J].
Chinese Journal of Endocrinology and Metabolism.
Volume 37, Issue 6, June 2021.
[3]Bharucha AE, Kudva YC, Prichard DO,et al.
Diabetic Gastroparesis[J].
Endocrine reviews , 2019,40（5):1318-1352.
[4]Chen Jiande, Cheng Jiafei.
New progress in pathophysiology and treatment of functional dyspepsia and gastroparesis[J].
Chinese Journal of Digestion,2021;1(15): 45-47.