The term “prokinetic” refers, strictly speaking, to molecules that stimulate gut motility through a direct effect on gut muscle itself or via the activation of its excitatory innervation; phenomena that can be studied in detail in the tissue bath but scarcely translate to clinical practice. A refinement of this concept that defines a prokinetic as an agent that “enhances coordinated gastrointestinal (GI) motility and transit of content in the GI tract, mainly by amplifying and coordinating GI muscular contractions” provides a better approximation to clinical need (1), as exemplified by the positive correlation, in gastroparesis, between an acceleration in gastric emptying (when optimally measured) and symptom improvement with promotility drugs (2). Success with a promotility approach has also been achieved in chronic idiopathic constipation; prucalopride, for example, has been shown to stimulate colonic motility, accelerate transit, and promote complete, spontaneous bowel movements (3). For functional GI disorders, however, this well-circumscribed concept may have little relevance, as few of these entities are based on reduced or absent muscle contractility alone but rather involve variable contributions from such phenomena as accommodation, tone, compliance, sensation, and brain-gut interaction; neuromodulation, rather than prokinesia, may be more appropriate (4). It must also be remembered that agents developed as prokinetics had other effects, be they desirable or undesirable, and may have owed their modest success in functional GI disorders to their “dirty” background (5).
WHAT IS AVAILABLE?
The simple answer in the United States right now is not a lot; agents that have been studied fall into 3 main drug classes:
- Dopamine antagonists (Table 1): these block inhibitory D2 receptors in the enteric and central nervous systems. Metoclopramide and levosulpiride also act as 5-hydroxytryptamine type 4 receptor agonists, which potentiates their prokinetic effects. An important advantage for some in this category, such as metoclopramide and domperidone, is a central antiemetic effect. Metoclopramide alone is available in the United States and remains the only drug approved by the FDA for the treatment of gastroparesis; domperidone is available in Europe, Canada, Mexico, and most Asian and South American countries, and levosulpiride is available in Europe, Mexico, and Asia. Bromopride and clebopride are not widely available, and clinical data on their use are limited. Dopamine antagonists have primarily targeted foregut syndromes. Major side effects with some drugs in this class include extrapyramidal symptoms, hyperprolactinemia, and prolongation of the QT interval (6).
- Serotonergic agonists (Table 2): agonists at the serotonin (5-hydroxytryptamine) type 4 receptor have been used for some time as prokinetic agents, with cisapride being the prototype (5). Cisapride was a true pan-gut prokinetic; it promoted esophageal peristalsis, augmented lower esophageal sphincter pressure, and accelerated gastric emptying and colonic transit. Variable efficacy was demonstrated in clinical trials in gastroesophageal reflux disease, functional dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, and constipation (5,6). Reports of serious arrhythmias related to QT interval prolongation led to its demise, and, for some time, cast a shadow over this drug class; fortunately, a number of seemingly safer options are now available (Table 2) but, in the United States, at least, are now primarily focused on the lower GI tract.
- Motilin receptor agonists: erythromycin has been the most widely used motilin receptor agonist in gastroparesis, although not approved by the FDA for this indication. While effective in the acute setting and when used parenterally, longer-term results have been disappointing due to tolerance. Alternative macrolides include azithromycin, which has been shown to stimulate gastric motility and accelerate emptying (8). Although it has some theoretical advantages over erythromycin (longer half-life, fewer drug interactions, and less propensity for QT segment prolongation), clinical trial data are limited, and it has never been approved for gastroparesis. Much effort has been exercised in the search for a nonantibiotic macrolide prokinetic—none has, as yet, gained approval.
- Cholinergics: bethanechol was, perhaps, the original prokinetic but lost favor because of side effects. Of late and prompted by the loss of other prokinetics, clinicians have turned to acetylcholinesterase inhibitors for promotility effects. Neostigmine is primarily used parenterally for the short-term treatment of acute colonic pseudo-obstruction (Ogilvie syndrome) and refractory constipation (9). Bradycardia can occur, and cardiac monitoring is recommended. Another cholinesterase inhibitor, pyridostigmine, administered orally, has shown efficacy in chronic constipation (10) and has been used, again off label, in gastroparesis (1). Acotiamide, a novel inhibitor of cholinesterase, has been shown to improve gastric accommodation and emptying in patients with functional dyspepsia (11) but has not been approved in the United States.
- Other agents: alvimopan, a peripherally acting mu-opioid receptor antagonist, has been approved by the FDA for short-term (15 doses) hospital use in patients undergoing partial large or small bowel resection with primary anastomosis to accelerate upper and lower intestinal recovery time (12). Because of a high number of myocardial infarctions in long-term alvimopan users, its distribution is tightly regulated and is available only through a restricted program (https://www.merckconnect.com/entereg/dosing-administration/?safety_overlay&gclid=EAIaIQobChMI0cfxzLv74wIVTv_jBx1PDgpNEAAYASAAEgLX3_D_BwE&gclsrc=aw.ds#ssi-safety). Relamorelin is a ghrelin agonist with prokinetic effects and has shown efficacy in gastroparesis and chronic constipation (13). Benefits for the herbal products STW-5 (also known as iberogast) and TU-100 (daikenchuto) have also been suggested in motility-related disorders, but whether they can be classified as prokinetics is unclear.
PROKINETICS IN CLINICAL PRACTICE: WHAT TO DO?
- What indications? Although prokinetics have shown variable efficacy in gastroesophageal reflux disease, gastroparesis, small intestinal dysmotility, chronic intestinal pseudo-obstruction, and “functional” disorders such as functional dyspepsia, chronic constipation, or irritable bowel syndrome with constipation, their most common indications in clinical practice are gastroparesis, functional dyspepsia, and constipation. Other indications include ileus, colonic pseudo-obstruction, to assist with visualization at upper GI endoscopy, reduce aspiration risk in relation to anesthesia or sedation, or facilitate the passage of GI tubes. Of these, the best evidence lies with gastroparesis and chronic constipation (1–3,6,7,14).
- Be aware of risks and how to avoid them. These are listed in Table 3. It is also vital to search for and correct any underlying and reversible cause of dysmotility and to exclude obstruction at any level.
- Review medications: several prescription or nonprescription medications impair motility: opiates, anticholinergics, and calcium-channel blockers, with effects often most pronounced in the elderly. It is also vital to be aware of potential drug interactions and, especially, of those that might potentiate QT prolongation.
- Choosing a prokinetic.
- Prokinetics have a largely unproven track record in functional dyspepsia (14) but may be of benefit if delayed gastric emptying is present (2) or symptoms suggest postprandial distress (7). In addition, agents with antiemetic effects may aid symptom relief.
- In gastroparesis, intravenous erythromycin (if it can be sourced) is effective in the acutely hospitalized patient, although long-term use is not recommended because of poor bioavailability of the oral formulation, tolerance, and antibiotic effects. Metoclopramide (available for administration via parenteral and oral routes) can also be used in the short term and remains the only drug actually approved for gastroparesis (for “symptom relief with acute and recurrent diabetic gastroparesis”), but because of the risk of tardive dyskinesia, its use should be avoided beyond 12 weeks. What are the alternatives? Domperidone is sourced by patients from Canada and Mexico and can be obtained through an expanded access investigational new drug application (https://www.fda.gov/drugs/investigational-new-drug-ind-application/how-request-domperidone-expanded-access-use). It too was the subject of a warning in Canada relating to associations with life-threatening arrhythmias and death. Other options? Right now, for prokinetic effects, I use pyridostigmine on an empiric basis, I am encouraged by the very recent data on the efficacy of prucalopride in gastroparesis (15), and I look forward to more data on tegaserod, velusetrag, and others (16).
- Prucalopride and tegaserod are currently approved for use in chronic idiopathic constipation and irritable bowel syndrome with constipation, respectively. Quite where they fit among the various available options remains unclear but should emerge as clinicians gain more experience with their role in clinical practice. Data on the use of prokinetics in special populations such as opioid-induced constipation (where several alternatives are approved) or constipation related to Parkinson disease are limited.
CONFLICTS OF INTEREST
Guarantor of the article: Eamonn M. M. Quigley, MD, FRCP, FACP, MACG, FRCPI.
Specific author contributions: Both V.G. and E.M.M.Q. researched and wrote the manuscript; both approved the final version.
Financial support: Supported, in part, by a bequest from the Josephine Hughes Sterling Foundation.
Potential competing interests: E.M.M.Q. has in the past served as an advisor to Janssen, Movetis, Shire, and Takeda and has received research support from Janssen, Shire and, Theravance.
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