J Neurogastroenterol Motil, Vol. 21 No. 3 July, 2015 pISSN: 2093-0879 eISSN: 2093-0887 http://dx.doi.org/10.5056/jnm15094 JNM Journal of Neurogastroenterology and Motility Review Prokinetics in the Management of Functional Gastrointestinal Disorders Eamonn M M Quigley Division of Gastroenterology and Hepatology, Department of Medicine, Houston Methodist Hospital, Houston, Texas, USA A variety of common and some not common gastrointestinal syndromes are thought to be based on impaired gut motility. For some, the role of motility is well defined, for others and the functional gastrointestinal disorders, in particular, the role of hy- po- or dysmotility remains unclear. Over the years pharmacological and physiological laboratories have developed drugs which stimulate gut motility; many have been evaluated in motility and functional disorders with what can best be described as mixed results. Lack of receptor specificity and resultant expected and unexpected adverse events have led to the demise of some of these agents. Newer, more selective agents offer promise but the heterogeneity of the clinical disorders they target continues to pose a formidable challenge to drug development in this area. (J Neurogastroenterol Motil 2015;21:330-336) Key Words Constipation; Dyspepsia; Gastroparesis; Intestinal pseudo-obstruction; Irritable bowel syndrome inadequate to address the contributions to symptoms of such fac- tors as dysmotility, visceral hypersensitivity and altered visceral Introduction tone, as well as changes in compliance and accommodation. The term prokinetic means simply to promote movement Hypomotility, the ideal target for a prokinetic, was unlikely to be and, in the context of the gastrointestinal tract, was introduced to relevant to all but a few rare disorders. Accordingly the field of refer to a class of drugs that promoted gastrointestinal motility study came to be renamed neurogastroenterology or, as in the case and, thereby, transit. This stimulatory effect was considered clin- of ANMA, neurogastroenteology and motility. Newer concepts ically relevant to the management of disorders characterized by such as enteric neuro-modulation emerged and agents whose pri- impaired motility, such as gastro-esophageal reflux (in some in- mary target was not motility but rather visceral sensation, for ex- stances), gastroparesis, intestinal pseudo-obstruction, and colonic ample, emerged. Also, with the emergence of new ideas relating inertia. However, as the complexity of symptom pathogenesis to the pathophysiology of such common disorders as irritable came to be understood and as the multifactorial nature of the bowel syndrome (IBS), a whole new set of therapeutic targets more functional gastrointestinal disorders came to light, such a came in to range; from the central nervous system to the enteric simplistic concept (stimulating motor activity) began to appear immune system and the gut microbiota. To cover all agents that Received: June 1, 2015 Revised: None Accepted: June 23, 2015 CC This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons. org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. *Correspondence: Eamonn M M Quigley, MD, FRCP, FACP, FACG, FRCPI Division of Gastroenterology and Hepatology, Houston Methodist Hospital, 6550 Fannin St, SM 1001, Houston, Texas 77030, USA Tel: +1-713-441-0853, Fax: +1-713-797-9595, E-mail: [email protected] Financial support: None. Conflicts of interest: None. ORCID: Eamonn M M Quigley, http://orcid.org/0000-0003-4151-7180. ⓒ 2015 The Korean Society of Neurogastroenterology and Motility 330 J Neurogastroenterol Motil, Vol. 21 No. 3 July, 2015 www.jnmjournal.org Prokinetics in the Management of Functional Gastrointestinal Disorders have been developed, or are in development, to address any one “motility” (such as functional dyspepsia [FD] and IBS) were de- or a combination of these factors is beyond the scope of this re- fined on the basis of symptom aggregations alone. As a con- view and the reader is referred to an elegant and recent review by sequence, it is undoubted that these entities contain heteroge- Camilleri1 for a more comprehensive overview of this area. neous patient populations and are likely to encompass a number Instead, this review will focus on those strategies which have been of pathophysiological processes.3 These were not, despite their developed to specifically address gastrointestinal motility and its frequency in the general population and resultant attractiveness to stimulation, in particular. pharmaceutical companies, good testing grounds for drugs that had a single primary effect: the stimulation of motility. Pharmaceutical companies were attracted nevertheless by the ap- The Prokinetic Approach: Challenges parently vast size of the “functional” market and pursued the de- Before enumerating the list of agents that have effects on mo- velopment of prokinetic agents. Not surprisingly, functional gas- tility and discussing their relative merits and shortcomings, it is trointestinal disorders have proven to be a virtual minefield for important that some challenges intrinsic to this class of com- such drugs. pounds be explored. Anyone who has worked in this area over the past several decades will have borne witness to the many trials and Non-selective Drugs Will Have Side Effects infrequent tribulations that have been associated with this area. We have learned repeatedly of the problems that seem to be So what are the problems? inevitably encountered when non-selective agents are used to pro- mote gut motility. Firstly, “dirty” drugs that interact with more Is the Simple Stimulation of Gut Motility a than one receptor in the gastrointestinal tract may induce a ple- Valid Target? thora of effects some desirable and others undesirable and, per- The focus of past research efforts on the synthesis and testing haps, even contrary to the expected primary action. Secondly, ef- of compounds that mimicked the major excitatory neurotrans- fects on other receptors will inevitably lead to unwanted side mitters of the gastrointestinal tract (such as acetylcholine) was effects. Thus the cholinergics could not be tolerated because of based on the assumption that reduced or absent motor activity bladder spasms and cisapride was withdrawn because of cardiac was fundamental to the pathophysiology and the genesis of symp- toxicity. In the latter example the effect was an unexpected one; toms in a number of apparently intractable disorders.2 Gastropa- an interaction with the Human Ether-a-go-go-Related Gene resis serves as an excellent example of the shortcomings of this (hERG) channel led to the occurrence of hERG channel-medi- approach. A primary target for many new prokinetic agents, gas- ated cardiac arrhythmias, such as Torsades de Pointes and ven- troparesis proved to be a most frustrating testing ground for nov- tricular tachycardia.4 Though many of these adverse events were el compounds as little correlation could be found between the ac- related to preexisting cardiac disease or the co-administration of celerating effects of various agents on gastric emptying and cisapride with drugs that either had similar effects on cardiac symptom responses. It is now apparent that factors other than the electrophysiology (prolongation of the Q-T interval) or that al- one that we can most readily measure, gastric emptying, must be tered the metabolism of cisapride, a few occurred in individuals involved in the generation of symptoms in affected individuals. who did not have obvious risk factors and led to the withdrawal of Similarly, constipation is now viewed as more than just infrequent the drug world-wide. All new compounds are now tested for Q-T bowel movements and a simple prokinetic action may not address effects.5 More recently and, perhaps more troublingly, toxicities the constellation of symptoms that are now included under the have appeared which are more difficult to explain, such as the rare umbrella of chronic idiopathic (or functional) constipation. instances of cardiovascular adverse events that led to the demise of tegaserod.5 For all of these reasons, the goal of modern drug Target Disorders Are Poorly Defined development in this area has been to attempt the highest degree In contrast to what might be termed the “classical” motility possible of receptor and tissue selectivity.6 disorders, such as achalasia, scleroderma, or Hirschsprung’s dis- ease where pathophysiology is well understood and therapeutic Regulatory Hurdles approaches can be accordingly developed, many of the disorders Chastened by their experiences with cisapride and tegaserod that crept under the flysheet and gained access to the tent that was (as well as with other drugs targeted at IBS such as alosetron and Vol. 21, No. 3 July, 2015 (330-336) 331 Eamonn M M Quigley cilansetron), regulatory agencies have raised the bar significantly brain barrier. Furthermore, metoclopramide is available for both when it comes to the approval of prokinetic and related drugs. On oral and parenteral use and in a generic form. Levosulpiride, a the assumption that the target disorders are not life-threatening, DA2 antagonist in development, has been shown to accelerate regulatory agencies have adopted a virtual zero tolerance stance in gastric emptying in diabetics and to improve glycemic control relation to serious adverse events