Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 66 No. 5 pp. 447ñ460, 2009 ISSN 0001-6837 Polish Pharmaceutical Society

REVIEW

PATHOPHYSIOLOGICAL CONCEPTS OF FUNCTIONAL DYSPEPSIA AND IRRITABLE BOWEL SYNDROME FUTURE PHARMACOTHERAPY

£UKASZ DOBREK* and PIOTR J. THOR

Department of Pathophysiology, Medical College, Jagiellonian University, 18 Czyst St., 31-121 KrakÛw, Poland

Abstract: The functional gastrointestinal diseases (FGIDs) are often noticed disturbances. Functional dyspep- sja (FD) is the most frequent FGID of the upper part of the gastrointestinal tract while irritable bowel syndrome (IBS) occurs in the lower gastrointestinal part. Both clinical entities are characterized by rich symptomatology and the patern of the diagnostic guidelines. Recognition and the classification of FGIDs are difficult, consisting in exclusion of all possible organic disor- ders and subordinating on the predominant symptom basis to most appropriate class, acording to Rome III clas- sification. The present FGIDs pharmacotherapy is limited mostly to the symptomatical treatment and it is based on med- icines conventionally used in various gastrointestinal organic illnesses (antisecretory, gastroprotective agents, antidiarrhoeal and laxative drugs). Some of them which seem to diminish visceral hypersensitivity acting via

serotonin receptors are also used, including 5-HT4 agonists and 5-HT3 antagonists. Many investigations over the new causal acting medicines last at present, which would be able to abolish the main pathophysiological FD and IBS mechanisms: visceral hypersensitivity and both myoelectrical and dysmotility phenomena. Thus, new pharmacological agents influencing opioid, purinergic, NMDA, CCK-A, or NK receptors are studied. The article is the mini-review, representing classification and the outline of the FGIDs pathogenesis, the pres- ent concepts of their pharmacological treatment and the future perspectives of pharmacoherapy with the use of new, interfering into key pathomechanisms drugs .

Keywords: functional gastrointestinal disorders (FGIDs), functional dyspepsia (FD), irritable bowel syndrome (IBS), future FGIDs pharmacotherapeutical options

Abbreviations: 5-HT ñ 5-hydroxytryptamine, serotonin, Ach ñ acetylcholine, CCK ñ cholecystokinin, CLC2 ñ chloride channel 2, CNS ñ central nervous system, CRF ñ corticotropin releasing factor, DLD ñ dysmotili- ty-like dyspepsia, ENS ñ enteric nervous system, EPAN ñ extrinsic primary afferent neurons, EPS ñ epigastric pain syndrome, FD ñ functional dyspepsia, FGIDs ñ functional gastrointestinal disorders, GIT ñ gastrointesti- nal tract, Hp ñ Helicobacter pylori, HPA ñ hypophysis-pituitary-adrenal (axis), IBS ñ irritable bowel syndrome, IPAN ñ intrinsic primary afferent neurons, MT ñ melatonin, NK ñ neurokinin, NMDA ñ N-methyl-D-aspartic acid, P2X ñ purinergic receptor, PDS ñ postprandial distress syndrome, SST ñ somatostatin, ULD ñ ulcer-like dyspepsia

The Functional Gastrointestinal Disorders toms, imitating organic background of observed FGIDs classification changes. However, their recognition requires exclu- sion of the organic disorder which could be the The definition of the functional gastrointestinal cause of these symptoms. The complexity of FGIDs disorder (FGID) is applied to the description of gas- symptomatology created the necessity of their clas- trointestinal symptoms, suggesting incidence of sification arrangement, based on pathophysiologi- organic disease, however, without morphological cal-anatomical criteria. In 1991 experts team created changes which could be responsible for felt ail- The Committee to Gastrointestinal Functional ments. FGIDs are affirmed in patients with both Diseases and they introduced the first FGIDs classi- upper and lower gastrointestinal tract symptoms. fication (Rome I) which was updated and replen- These diseases are characterized by the occurrence ished about new guidelines, diagnostic criteria and of various dyspeptic, dysmotility and pain symp- patern of therapeutic conducts in definite individuals

* Corresponding author: e-mail: [email protected]

447 448 £UKASZ DOBREK and PIOTR J. THOR in 1999. Since this year, Roman Criteria II were criteria, was a new functional dyspepsia (FD) cate- regarded to be the most common accepted consen- gorization into the postprandial distress syndrome sus, applied in everyday clinical practice and scien- (PDS) and the epigastric pain syndrome (EPS). PDS tific investigations. substituted the earlier used dysmotility-like dyspep- Rome II classification favored 7 principal sia (DLD) term, while EPS replaced previously dis- FGIDs groups: functional disorders of esophagus, tinguished ulcer-like dyspepsia (ULD) (2, 3). stomach and duodenum, intestines, the functional stomach pain, the bile tract dysfunctions, the func- The epidemiology of the functional gastrointesti- tional disorders of the rectum and functional pedi- nal diseases atric diseases. In every group, the next subclasses The epidemiological data show that the fre- are distinguished, according to the predominant quency of FGIDs occurrence is similar both in the symptom and in relationship with this suggested Western and Central Europe countries and in the pathophysiological background (1). USA with lower incidence in Asiatic region. Among The Rome II guidelines found necessity of all functional diseases, functional dyspepsja (FD) occurrence in 12 months span previous FGIDs and the irritable bowel syndrome (IBS) are the two recognition (lasting for the least 12 weeks in the most frequent clinical cases. Functional dyspepsja period of the observation), definite ailments about occurs particularly often. Estimating generally, the the predominant character, allowing to the accom- frequency of the FD occurrence is between 11.5- plishment of patient to one from distinguished 29.2%. About 20% inhabitants of Europe and USA groups qualification (1). suffer from the dyspeptic complaints and pharma- The progress of medical knowledge, which cotherapy was applied in 50% of all of them by the happened during last years in pathophysiology, general practitioners. The postprandial distress syn- diagnosing and the treatment of the functional gas- drome (previously identified as dysmotility-like dys- trointestinal diseases together with the existing pepsia ñ DLD) occurs mainly in adult patients, usu- interpretative divergences caused the necessity of ally in the age below 59 years. The epigastric pain Rome II guidelines reanalysis. The new Rome III syndrome (in the former nomenclature identified classification, based on updated Roman II one, was with ulcer-like-dyspepsia, ULC) is often observed in announced in year 2006. The Rome III criteria, patients close to 40 years. Thus, the top of FGIDs favors 28 FGIDs disturbances in adults and 17 pedi- clinical manifestation falls on 40-50 year of the life. atric figures. Similarly as in Rome II classification, The majority of studies did not show the differences it is based on predominant symptoms present in par- in the frequency of FD occurence in men and ticular patients without different organic disorders. women, although several investigations revealed an However, certain histological changes were demon- increased FD incidence in females, especially with strated last years in some FGIDs; therefore it ques- neurotic disturbances. In the analysis of influence of tioned their only functional character. At present, the potential risk factors on the FD occurrence, according to Rome III arragement, FGIDs are divid- essential differences were not found for smoking, ed into 8 main groups: 6 for adults and 2 for chil- increased alcohol intake, applying vegetarian diet, or dren. When compared to the previous Rome II, prin- excessive drinking of coffee or strong tea. FD attend- cipal changes were introduced in B class (containing ed with the equal frequency in patients exhibited and gastroduodenal disturbances) and F class related to not exposed on exchanged factors. There were also the rectal functional illnesses. The E class (describ- no differences in FD occurrence in persons with var- ing the functional disorders of bile tract) was also ious socio-economical status. Taking under consider- widen and the completely new division of the hith- ation the influence of non-steroidal antiinflammatory erto existing class G (Rome II pediatric FGIDs) was drugs (NSAID), the enlarged EPS frequency was dis- executed, distributing it on two classes G (neonates covered in patients taking these preparations regular- and babies) and H (children and adolescents). The ly. The influence of the Helicobacter pylori (Hp) next change in Rome III consensus, in the compari- infection was ambiguous. In the study published in son to previous Rome II directives is the time of 2000, it was discovered that among patients with the symptoms duration. Nowadays, it is recommended evidences of Hp infection (without coexisting organ- to get in the diagnostic process the confirmation of ic changes ), 44% of them felt the dyspeptic ailments the FGIDs symptoms occurrence by 6 months previ- in the comparison with 36% with the negative Hp ous to the recognition. Additionally, they should be status. However, other reports also exist, supporting kept in active form for 3 months. Moreover, one of the thesis that Hp is not the essential risk factor of the the most important changes, introduced in Rome III FD development. This research subject is still Pathophysiological concepts of functional dyspepsia and irritable... 449 explored and numerous investigations dedicated to are also interesting findings ñ in IBS patients the the influence of the Hp infection on FD and other hyperreactivity of the HPA axis was observed (2). gastrointestinal disorders development are conducted (3, 4). Psycho-social factors The irritable bowel syndrome (IBS) is the next The investigation over the influence of psy- most common functional disorder. This syndrome chosocial factors in FGIDs patients revealed that occurs in about 10-15 % the adult European popula- stress is the factor sharpening the FGIDs course. In tion, athough the epidemiological data are various FGIDs patients, especially with IBS ones, enlarged depending on accepted diagnostic criteria (some emotional and neurotic lability is usually observed, reports give even 30% IBS incidence). IBS is contributing to functional gastrointestinal changes defined as the functional disease with chronic or as a result of the central influence on the enteric recurrent lower abdominal discomfort together with innervations. The sharp stress is the recognized fac- consipation/diarrhoea and bloating which do not tor changing motor and secretory activity of the gas- have the organic background [acc. to Patterson et al. trointestinal tract through neuroendocrine mecha- (5)]. There are also Manningís criteria, especially nisms. The influence of the chronic stress on the useful in the common ambulatory practice in IBS FGIDs development is not so obvious, because of diagnostic procedure. They include the features the fact that chronic gastrointestinal ailments felt by which occur in the changing combination in IBS the patient can be the cause of the observed neurot- patients: the abdominal pain relieved by defecation, ic disturbances. The larger intensification of anxiety, the changes of the defecation rhythm together with depressive and neurosis disorders marks patients the feeling of the incomplete defecation, the feeling with FGIDs without all doubts. This finding is con- of rectal distension and the presence of mucus in sistent with the hypothesis of visceral hypersensitiv- feces (1-3). ity described further. However, the relationship In the case of every FGIDs, alarming symp- between neuropsychiatric disorders and the FGIDs toms suggesting the serious organic disease, such as: symptoms is not so visible in FD patients like in the loss body weight, anemia development, chronic patients with IBS (2, 7). fever, family gastrointestinal cancer occurrence in medical anamnesis, the non-specific inflammatory The influence of the bacterial flora intestinal diseases can not accompany functional The influence of Helicobacter pylori (Hp) dyspeptic or intestinal symptoms. One should also infection in the FGIDs pathogenesis is often an keep the special caution in IBS and FD diagnosing explored problem at present, especially in FD. Large in patients in the age above 50 (5, 6). epidemiological investigations showed the enlarged incidence of the Hp infection in patients with ulcer- Pathophysiology of the gastrointestinal function- like dyspepsia (Rome II) ñ epigastric pain syndrome al diseases (Rome III) in the comparison to the healthy control, although when studying the patients with the PDS Genetic predispositions such dependence was not revealed. Thus, there is Genetic factors may predispose some patients still no agreement with the opinion confirming the to the FGIDs development although their clinical essential Hp influence on the FGIDs development. expression depends on various environmental fac- The proofs confirming the undeniable Hp role in tors. The role of genetic factors may be seen in FGIDs pathogenesis exsist. It is known that the Hp reducing the antiinflammatory cytokin (Il-10, TGF- changes APUD gastric neuroendocrine cells density β) level, what was affirmed in IBS patients. The (mainly G cells (growth) and D ones (fall)) and decrease of antiphlogistic cytokin may result in causes an increase of the gastric secretion through enlarged intestinal sensitization. Moreover, in IBS before- and postprandial hypergastrinemia and the patients genetic polymorphism associated with the lowering of the somatostatin level. The next evi- proteins of the synaptic serotonin reuptake system dence of gastric secretion disturbances in Hp infect- was discovered, as well as the polymorphism of ed patients was obtained after intravenous adminis- adrenergic alpha receptor which affects the intestin- tration of the gastrin releasing peptide (GRP) in al motility. The family incidence of the FGIDs patients with the peptic ulcer. There was almost a occurrence is also observed and this fact additional- sixfold increase of the acid secretion in Hp positive ly underlines their potential genetic predispositions. participants when compared to patients without Hp The genetic-induced differences of the axis hypo- infection. Despite these findings, there are also con- thalamus-pituitary-adrenal (HPA) glands activity traindicant results of Hp eradication on the gastric 450 £UKASZ DOBREK and PIOTR J. THOR secretion and the dyspeptic ailments which do not transmitors, plays essential role in gastrointestinal allow to accept the thesis about the positive eradica- motility, secretion and absorption. The special atten- tive treatment effects (8-10). tion is paid to the afferent part of ENS (especially to There are also reports that the excessive colo- intrinsic primary afferent neurons; IPAN which play nization of the lower part of the gastrointestinal tract major role in local intestinal reflexes generation and (GIT) with the non-physiological bacterial flora dis- extrinsic primary afferent neurons; EPAN, which poses to the IBS development. The improvement of modulate gastrointestinal functions via central path- intestinal symptoms in response to Bifidobacter ways). This afferent system is regarded to be co- infantis administration, as a result of the proinflam- responsible for visceral hypersensitivity and local matory Il-12 level decrease and the increase of the neurogenic inflammation development (12, 13). The antiinflammatory Il-10 was observed in one of the brief description of ENS neurons is given in Table 1 research study. The problem of the both probiotics and the neuronal organizaton in gastrointestinal wall and prebiotics influence, is now widely discussed. It is presented in Figure 1. seems that they could be used as the modulators of the pharmacological therapy, although it requires Disturbances of the gastrointestinal tract motility further studies (11). In healthy subjects, strong emotions or envi- ronmental stress lead to an increase of the GIT Disturbances of the paracrine gastrointestinal motility. In FGIDs patients, the stronger motility activity, the development of local inflammatory response in comparison to the healthy controls in reaction and enteric nervous system dysfunction similar conditions was observed. The metaanalysis of 17 cohortal investigations conducted in 2000 In patients with FGIDs, the enlarged activity of showed the essential delay of gastric emptying in inflammatory cells in the gastrointestinal wall and almost 40% FD patients. The lack of the postprandi- the increased proinflammatory cytokins level were al accommodation of the proximal stomach is the revealed. Moreover, in about 1/3 of patients suffer- next characteristic dysmotility finding in patients ing from FD or IBS, the convergence of the FGIDs with postprandial distress syndrome. Gastric scintig- development and the experienced sharp inflamma- raphy, ultrasonography and barostatic measure- ble episode was confirmed. It seems very probable ments showed the disturbed intragastric food distri- that even chronic subinflammatory condition con- bution in PDS patients, with the accumulation of tributes to visceral hypersensitivity in FGIDs gastric content in the distal stomach together with patients. the reduced relaxation of the antral region. An increase of the neurotensin, as well as Duodenal dysmotility is the next pathological alter- cholecystokinin and gastrin with a decrease of native in FD and IBS patients. These pathological secretin and vasoactive peptide secretion was changes may arise from the disturbed myoelectrical proved in IBS patients. The IBS patients were also activity which is the key organizer of the gastroin- characterized by intensive mastocytes and lympho- testinal motor activity. Gastric dysrhythmias (both cytes infiltration of intestinal wall. It resulted in brady- and tachyarrhythmias) were disclosed in enlarged histamine, methylhistamine and tryptase electrogastrographic (EGG) studies, with a decrease intestinal wall increase. What is also of essential of the physiological gastric slow wave time and the meaning, mastocytes and other inflammatory state lack of suspected postprandial amplitude power cells were found nearly the submucosal plexus. increase. All those observations confirm depend- Neurons of this structure may be stimulated through ence between the early satiety, nausea and vomiting the inflammatory mediators, released from the in FD patients and dysmotility of the upper gas- inflammatory cells. The suspected neuroendocrine trointestinal tract (2, 10, 13). interactions between the inflammatory mediators and the afferent endings are regarded to be factors Visceral hypersensitivity contributing to the primary visceral hypersensitivity The visceral hypersensitivity is proposed as a development (11, 12). The submucosal plexus key hypothesis, explaining the development of func- together with myenteric one are parts of the enteric tional gastrointestinal diseases. This phenomenon is nervous system (ENS). The ENS has extremely based on the altered peripheral mechanisms. complex structure, containing lots of different neu- Visceral sensations are transmitted from GIT to the rons connected by internal junctions and creating brain, where the pain sensations are perceived. The connections with the neurons of external autonomic enhanced central pain perception may arise from an innervation. ENS, acting via releasing many neuro- increased signal from the gut, the ampflication of a Pathophysiological concepts of functional dyspepsia and irritable... 451 normal GIT signal during its travel through the sensitivity as an accompanied phenomenon (esti- spinal cord and brainstem (14, 15). An interesting mated by a cold-water tolerance test) was identified observation accomplished in FD subpopulation was in about 30-50% of FGIDs patients. The mechanism demonstrating enlarged sensibility to isobaric or iso- of visceral hypersensitivity is also associated with volumetric balloon distention of the proximal stom- central mechanisms. Studies of both visceral and ach together with the epigastric pain. The increased somatic pain have demonstrated brain regions susceptibility of the stomach wall on the expansion involved in the affective, cognitive and emotional indicates the dysfunction of the afferent activity. aspects of pain experience which are also connected There are also studies suggesting the role of distal with autonomic nervous system centers. It is likely stomach hypersensitivity in the pathogenesis of the that the perception of peripheral changes from the dyspeptic ailments. Thus, the generalized disturbed GIT are filtered and modulated by central mecha- gastric afferents activity may be responsible for pro- nisms, including central amplification at the level of ducing the dyspeptic symptoms. Similar results in the spinal cord or the brain. The cortico-limbic-pon- the balloon test with distal colon extension was tine brain regions are the crucial central part of the showed in IBS patients. Moreover, FD subjects were enhanced perception of peripheral stimuli. also characterized by the intensive motility response Moreover, the dependence between neuroticism and after intestinal chemoreceptors stimulations. The psychiatric disorders is observed. The possible intraduodenal application of the acid solution caused reciprocal interaction may exist between psychoso- the nausea and the reduced duodenal motility, cial factors and GIT sensorimotor function; the resulting in effective decrease of the exogenous acid reciprocal connection between the brain and the gut clearance. Both IBS or FD symptoms are known to (brain-gut axis). This hypothesis implicates that psy- occur after irritation of the gut by infectious agents, chological factors may influence gastrointestinal after rectal instillation of glycerol, while they may sensitivity. The idea of the bidirectional communi- be diminished by rectal administration of lidocaine cation system between the enteric nervous system (15). It is probable that visceral hypersensitivity is and the central nervous system (see Figure 2) is a not the regional mechanism, occuring only in the key target of future FGIDs treatment. The ENS and seperated fragment of the gastrointestinal tract, but CNS communicate through neural (autonomic nerv- it is the generalized phenomenon. Somatic hyper- ous system), neuroendocrine (HPA axis) and neu-

Figure 1. The diagram of ENS structure 452 £UKASZ DOBREK and PIOTR J. THOR

Figure 2. Visceral hyperalgesia diagram

roimmune pathways which may interact mutually. ed in peripheral or central part of the brain-gut axis Gastrointestinal sensory information is transmitted are expected to be introduced in clinical practice. to CNS through vagal and spinal afferent nerves They are briefly mentioned further. while central descending nerves include both excita- Table 2 represents the recapitulation of patho- tory and inhibitory pathways. The plurality of vari- genesis factors playing the part in the FGIDS devel- ous neuromediators involved in brain-gut axis func- opment. tioning enables new pharmacological points of inter- est. Moreover, the afferent endings play an addition- The symptomatology of the functional gastroin- al secretory role ñ they release many modulatory testinal disorders compounds which act via paracrine and autocrine mechanisms, leading to local neurogenic inflamma- The FGIDs symptomatology is very rich. tion development and lowering the pain threshold FGIDs of the upper part of the gastrointestinal tract (16). It has been demonstrated that upregulation of are characterized by pyrosis, non cardiac chest pain, P2X, NMDA, AMPA, neurokinin (NK) or capsaicin epigastric pain (symptom predominant in EPS), the (TRPV1) receptors play an importamt role in both feeling of postprandial fullnes after even small meal, central and peripheral hypersensitivity (16, 17). belching, nausea and vomiting (particularly in PDS). Thus, in close FGIDs future therapy, acting or According to Rome III criteria, these complaints blocking agents of new discovered receptors situat- should appear 6 months and last by 3 months before Pathophysiological concepts of functional dyspepsia and irritable... 453

Table 1. The most important neurons and chemical neurotransmission in the enteric nervous system (ENS) (13, 14) ENS neuron Neurotransmiter Function IPAN (Intrinsic Primary Activated by mechanic or chemical stimuli, Acetylcholine Afferent Neurons) initiate peristaltic and secretory reflexes EPAN (Extrinsic Primary Central pain perception emotional Acetylcholine Afferent Neurons); and behavioral pain perception components Ascending myoenteric Acetylcholine, Substance P Activate ascending motor neurons neurons Descending myoenteric Acetylcholine, Substance P, ATP Activate descending myoenteric motor neurons neurons , Ascending (excitatory) Triggering contraction of smooth muscle myoenteric Acetylcholine, Substance P motor neurons proximal to their cells bodies

via muscarinic M3 and NK1 receptors Vasoactive intestinal peptide, Descending (inhibitory) Triggering relaxation of smooth muscle Nitric oxide, Neuropeptide Y, myoenteric motor neurons distal to their cells bodies ATP, GABA Submucosal ganglion Acetylcholine Elicit vasodilatation and glandular secretion neurons Modulatory myoenteric Elicit presynaptic activation of acetylocholine Serotonin neurons release via D2 receptors Modulatory myoenteric Elicit presynaptic inhibition of acetylocholine Dopamine neurons release via 5-HT4 receptors

Enterochromatoffin cells Serotonin Activate IPANs via 5-HT3 receptors Mediate influence of ENS neurons on smooth Interstitial cells of Cajal Nitric oxide muscle, organize myoelectrical activity

Table 2. Proposed pathomechanisms contributing to the functional gastrointestinal disorders (FGIDs) development

● Postprandial antral motility decrease ● Gastric fundus relaxation decrease Gastrointestinal dysmotility ● Gastric emptying rate decrease ● Gastric myoelectrical activity decrease

● Increased perception to gastrointestinal wall stretching Visceral hypersensitivity, ● Increased sensitivity to chemical stimulation ENS disturbances ● Chronic inflammatory reaction development Acid hypersecretion

● Acid hypersecretion Helicobacter pylori infection ● Neuroendocrine cells density alternation ● Dysmotility ???

● Acute stress Stress ● Chronic stress ???

● Anxiety disorders Psychiatric disturbances ● Depressive disorders ● Neurotic disturbances

Genetic predispositions ● Family incidence of FGIDs

making the diagnosis of the gastrointestinal func- co-exsistence combination of such symptoms as: tional disease. pain of the lower abdomen, discomfort in abdominal The special FGIDs figure affecting the lower cavity, bloating, the change of the defecation rhythm part of the gastrointestinal tract is the irritable bowel (diarrhoea or constipation) although the defecation syndrome (IBS). It is characterized by returning or causes the temporary improvement of felt ailments. 454 £UKASZ DOBREK and PIOTR J. THOR

Table 3. Class of medicines applied in current FD pharmacotherapy Pharmacological class Drug examples Effects Hp eradicative medicines The pattern of medicines containing: Hp eradication, indirectly dysmotility Aminopenicillin, Macrolide, PPI improvement and secretolytic Neutralizing agents Magnesium salts Gastroprotection, an acid excess neutralization Aluminium salts oraz hypothetic antiinflammatory Bismuth salts Gastroprotection, an auxliary agent in Hp eradication Sucralfat Gastroprotection, hipothetic antiinflammatory Prokinetics Metoclopramide, Cisapride Prokinetic and antireflux Proton pump inhibitors Omeprazole, Pantoprazole, Antisecretory and in Hp eradication (PPI) Lansoprazole, Rabeprazole

Antihistaminic H2 agents Ranitidine, Famotidine Antisecretory and partly antiinflammatory Tricyclic antidepressive agents Antidepressive drugs SSRI (Selective Serotonin Reuptake Inhibitors) Tymolepic, antidepressive and anxiolytic Anxiolytics Benzodiazepines Buspirone

Table 4. Class of medicines applied in current IBS pharmacotherapy Pharmacological class Drug examples Pharmacological effect Mebeverine, Scopolamine, Smooth muscle relaxation through anticholinergic Spasmolytics Dicycloverine, Cymetropium, effect or calcium channels blockade Pinaveryne Opioid µ and κ peripheral receptors agonists Loperamid ñ decreasing of gastrointestinal motility and Antidiarrhoeal agents Diphenoxylat sphincter tone increasing, additionally antinociception Increasing intestinal osmotic load, decreasing Laxative agents Lactulosum water reabsorption , peristaltic movement acceleration

5-HT4 receptor stimulation, increase of intestinal Tegaserod motility, CGRP and SP releasing ñ prokinetic 5-HT receptor agonists 4 Prucalopride effect in constipation-predominant IBS form

Ondansetron 5-HT3 receptor antagonists decreasing of ENS 5-HT3 receptor antagonists Granisetron stimulatory neurotransmitters releasing: Alosetron Ach, SP ñ antiemetic and antidiarrhoeic Serotonin Selective Reuptake Antidepressive agents Inhibitors (SSRI) Tricyclic antidepressive agents Central antinociception

Anxiolytics 5HT1A receptor agonists (Buspirone)

As it was mentioned earlier, despite the validated of the rectum, mucus in the stool). qualitative and quantitative diagnostic features pre- It should be noticed that the recognition of every sented in Rome III policy statement, the Manningís FGIDs is done as a diagnosis by exclusion. It means, IBS criteria still are used in the general clinical prac- that all possible coexisting diseases which could be tice (they include six main features: the chronic the cause of the ailments should be excluded in the lower abdominal pain connected with the defeca- diagnostic proceedings. It does not mean automati- tion, which causes the temporary improvement ail- cally, that no different organic gastrointestinal dis- ments, diarrhoeas, constipations or mixed figure, the ease can accompany the functional disease in the feeling of incomplete defecation and the distension same patient or that several functional disorders can Pathophysiological concepts of functional dyspepsia and irritable... 455

Table 5. New classes of medicines in FD treatment Pharmacological class Expected effect Prokinetics A. Dopaminolytic

Domperidone, Itopride, D2 receptors blockade and 5-HT4 receptors activation. Levosulpiride Gastric emptying rate acceleration, increasing B. Serotoninergic in antrum motility, antiemetic properties Mosapride, Tegaserode C. Motylin analogues Erytromycin, ABT229 κ- Agonists Visceral hypersensitivity and visceral pain decrease Fedotozine, Asimadoline P2X receptor antagonists Visceral pain decrease (Antinociception) NMDA receptor antagonists Visceral pain decrease (Antinociception) Vanilloid receptor agonists Visceral pain decrease (Antinociception) SST receptor agonists Motility and secretion functions modulating Oktreotyd CCK receptor antagonists Motility increase, visceral pain decrease (Antinociception) Loxiglumide

NK1 receptor antagonists Aprepitant, Ezlopitant

NK2 receptor antagonists Strong prokinetic and antiemetic effects (Antinociception) Nepadutant, Saredutant

NK3 receptor antagonists Talnetant CRF receptor antagonists Motility and secretory disturbances due to stress Antalarmin and HPA axis hyperreactivity modulation

not coexist at one patient. It widens considerably the ● Behavioral therapy symptomatology of FGIDs and make their diagnosis ● Biofeedback more difficult (2, 5, 7). ● Hypnotherapy 3. Vegetable preparations ñ phytotherapy The present pharmacological approach in FD and ● Capsaicin IBS treatment ● STW 5 The present therapeutic options in functional dys- Generally, these therapies were not subjected pepsia treatment include both non-pharmacological to the critical, unambiguous opinion, according to methods (of still unproved effectiveness), and phar- Evidence Based Medicine (EBM) principles. Thus, macotherapy with the use of traditionally applied their effectiveness and applying indications are con- groups of medicines (which are administrated not troversial. Among them, herbal preparation STW5 only in the FD treatment, but also in other diseases as the auxiliary phytomedicine is one of better stan- of the gastrointestinal tract) (18). dardized methods. It contains extracts from Non-pharmacological methods, being the optional, chamomile, mint, lemon balm, caraway seed and additional strategy in the FD therapy include: licorice. It was showed in wide conceived, doubly 1. Dietetic modifications blinded and randomized clinical investigation, that ● Consumption of more frequent but of small- after 8 weeks of the treatment in about 40% patients er volume meals receiving STW5, the essential decrease of dyspeptic ● Avoidance of meals in evening and night symptoms was affirmed. The exact pharmacological hours action of the components present in that preparation ● Limitation in consuming fatty meals was not discovered, however, spasmolitic and anti- 2. The psychological therapy inflammatory effects are postulated. The results of ● Relaxative therapies and teaching of coping the investigation of the capsaicin use ñ the active with the stress component of the chilli ñ are also encouraging 456 £UKASZ DOBREK and PIOTR J. THOR

Table 6. New classes of medicines in IBS treatment Pharmacological class Expected effects Potential application Prokinetics Gastrointestinal motility increase A. Dopaminolytic Constipation predominant IBS (mostly upper part) Domperidon B. Serotoninergic Gastrointestinal motility increase Norcisapride, Renzapride, Constipation predominant IBS (mostly lower part), Antinociception Mozapride, Tegaserod

C. Antiserotoninergic 5-HT3 receptor antagonists, Alosetron, Cilansetron Gastrointestinal motility decrease Diarrhoea predominant IBS Cholinolytics M3 receptor antagonists, lower (anticholinergic agents) Diarrhoea predominant IBS gastrointestinal part motility decrease Darifenacyne, Zamifenacyne Serotoninergic and noradrenaline agents SSRI (Selective Serotonine Reuptake Inhibitors) Antinociception Both IBS forms SNRI (Serotonine Noradrenaline Reuptake Inhibitors) Opioid receptor agonists Opioid µ and κ agonists Loperamide, Fedotozine, Diarrhoea predominant IBS Gastrointestinal motility decrease Asimadoline Opioid receptor antagonists Opioid µ antagonists Alvimopan Gastrointestinal motility increase Constipation predominant IBS α Adrenergic receptor 2 Antinociception Both IBS forms agonists Clonidine, Lidamidine CCK receptor antagonists CCK-A receptor antagonists Loxiglumide, Proglumide Mass intestinal movements generation Constipation predominant IBS NMDA receptor antagonists Antinociception Both IBS forms Dizocilpine, Memantine

NK receptor antagonists NK1 receptor antagonist, Ezlopitant gastrointestinal motility decrease and antinociceptive effect

NK2 receptor antagonist, gastrointestinal Both IBS forms Nepadudant motiliy decrease and probable antinociceptive effect ClC-2 chloride channel Apical chloride channels of the intestinal activators cells activation, gastrointestinal Constipation predominant IBS Lubiproston motility and secretion increase

because its use brought the improvement in some different ones revealed lack of such effect (21-24). FD patients (18-20). The traditional pharmacological interventions based The current guideline of the pharmacological on the most often applied medicines are given in FD therapy are based on the use of anti-acid neu- Table 3. tralizing agents, gastroprotectives medicines, secre- In the second most widespread functional gas- tolytics, prokinetics and antidepressant together trointestinal disorder, the irritable bowel syndrome, with anxiolytic drugs as supplementary medicines the recommended guidelines of the therapeutic strat- (especially in patients suffering from stressed emo- egy also exist. The applied pharmacotherapy tional lability). Pharmacological Helicobacter pylori depends on the predominant clinical IBS feature eradication in FD patients with positive Hp status is (diarrhoea-predominant IBS, constipation-predomi- still controversial. The part of investigations indi- nant IBS, mixed IBS figure). Similarly as the in the cates on insignificant, but the characteristic advan- FD case, non-pharmacological and conventional tage resulting from the eradicative treatment, while treatment methods are available (25, 26). Pathophysiological concepts of functional dyspepsia and irritable... 457

Non-pharmacological, additional methods include: treatment. 5-HT4 receptor agonists stimulate the 1. Dietetic modifications release of neurotransmitters and increase colonic ● The diet rich with vegetables, fruits, cereal motility, providing a rationale for their use in con- seeds stipation predominant IBS. The next drug ñ ● The diet containing wheat bran tegaserod (Zelnorm), a partial 5-HT4 receptor ago- 2. The psychological therapy nist was approved for IBS and constipation but ● Relaxative therapies and teaching of coping removed from the market in March 2007 because of with the stress cardiovascular side-effects. It has been subsequent- ● Behavioral therapies ly reintroduced under an investigational new drug ● Biofeedback protocol. It was also discovered, that 5-HT3 antago- ● Hypnotherapy nists such as alosetron, ondansetron, granisetron 3. Application of probiotics modulate visceral afferent activity and may improve ● Lactobacillus plantarum abdominal pain. In clinical trails these drugs were ● Bifidiobacterium breve effective in diarrhoea-predominant IBS. However, ● Streptococcus faecium alosetron was associated with ischemic colitis and Particularly interesting seems to be the therapy serious complications related to severe constipation, with use of non-pathological microorganisms. The prompting the Food and Drug Administration mechanisms explaining the partial withdrawal of (FDA) to remove it from the market in the United intestinal ailments in patients applying probiotic States. Evaluation of post-marketing data and preparations are only partly known and require fur- demand from a subset of patients who had respond- ther investigations. An increase of antiinflammatory ed to treatment has prompted the FDA to bring the mediators level was showed, such as Il-10, together drug back to the market under control (32-35). with a decrease of proinflammatory TNF-α and Il-8 Tricyclic antidepressants, and selective serotonin production. Moreover, probiotic bacteria showed reuptake inhibitors (SSRI) are also often used in the ability to the bile acids deconiugation (an excess patients with suspected visceral hypersensitivity. of these compounds was observed in patients with Amitriptyline in depressive FGIDs decreased viscer- diarrhoea-predominant IBS figure). The production al sensitivity but psychotherapy also improved of small-chain fatty acids, which have the ability of symptoms without any change in visceral hypersen- the induction of propulsive intestinal cramps and sitivity. SSRI used in healthy subjects did not accelerating the intestinal transit seems to be also of change sensitivity to gastric or colonic distension. essential meaning (27, 28). Moreover, some evidence suggests that the mixed Conventional IBS pharmacotherapy includes serotonin and noradrenaline reuptake inhibitors several groups of drugs, introduced in Table 4. (SNRI), such as wenlafaxine, can reduce sensations during colonic distention in healthy volunteers. Current serotoninergic and non-serotoninergic Thus, the results of the studies on serotoninergic targets in the pharmacotherapy of visceral hyper- antidepresants and their potential beneficial effects sensitivity as major FGIDs pathophysiological in FGIDs patients are still contradictory (29-31). factors The next drugs widely used in IBS are mebev- erine, pinaverine and trimebutine, classified as The most important goal of both IBS and FD direct smooth muscle spasmolytic agents. The last present and future pharmacotherapy seems to be the one acts via peripheral gastroduodenal opiod recep- visceral hypersensitivity. Several targets on afferent tors and modulates some neuropeptides releasing nerves for the treatment of visceral hypersensitivity (gastrin, motilin, VIP). These drugs, similar to cis- were identified, including 5-HT3, 5-HT4, opioid and apride, increase gastroduodenal motility and addi- α-adrenergic receptors (29-31). These drugs also tionally diminish intestinal sensitivity and affect improve gastroduodenal motility, thus, considering intestinal smooth muscle relaxation. The drugs men- their evident pharmacological effect, they are nowa- tioned above are also included in Table 4. days classified as prokinetics agents (and not ìanti- hypersensitiveî ones). The future therapeutic perspectives in functional The drugs affecting the hypersensitivity phe- dyspepsia and irritable bowel syndrome treat- nomenon inlude limited amount of serotoninergic ment agents (both 5-HT3 antagonists and 5-HT4 agonists), such as Cisapride. It was one of the first serotonin- The present FGIDs pharmacotherapy is diffi- ergic agents (5-HT4 agonist) registrated in FGIDs cult and often does not allow the achievement of 458 £UKASZ DOBREK and PIOTR J. THOR desired effect. Because of the fact that FGIDs patho- ing (through the influence on CCK-A receptors logical background is very complex without the pos- located on afferent vagal fibers) and co-introduces sibility of the indicating of predominant pathomech- the visceral pain. The phenomenon of hypersensitiv- anism, the nowadays therapy has only the empirical ity to CCK and the intensified interaction between character. Comparatively small quantity of the serotoninergic and CCK neurotransmission was also accessible Ñpharmacological basketî of medicines discovered in FD patients. In 90% of studied dedicated to applying in FGIDs is the next problem. patients, intensified dyspeptic effects after synthetic Increasing knowledge in neurogastroenterology, CCK analogue administration and their withdrawal structural organization and ENS function and mutu- after CCK antagonist application ñ loxiglumide al interactions between ENS and CNS, enable the were demonstrated. It is a strong proof convincing new possibilities of the pharmacological approach in that CCK is the next potent pharmacological link the FGIDs therapy. New substances acting to the between dyspeptic ailments and molecular pathome- influence on the brain-gut axis are now in the circle chanisms. Thus, CCK antagonists are seem the next of interests (29, 36, 37). promising direction in the searches of new medi- In the functional dyspepsia treatment, (mostly cines dedicated to the FD treatment. The possibility in the EPS therapy), new medicines with antinoci- of tachykinin (substance P, neurokinin A, B ñ NKA, ceptive properties are investigated. The κ-opioid NKB) pathway modulation is a second interesting receptor agonists are one of the promising groups of solution. Experimental investigations revealed medicines. Fedotozine and Asimadoline are the antiemetic effects of the NK-1 antagonist ñ aprepi- studied representatives of this group and the pre- tant. It gives the hope to the future application of this liminary results demonstrated the softening effect drug as antiemetic medicine during the cytostatics on visceral pain. The next potential action point of treatment in neoplastic patients. Moreover, NK-1 medicines affecting visceral hypersensitivity are antagonists also have antinociceptive effects and other receptors situated on afferent sensory vagal probably possess other additional influences on the and sympathetic fibres. Purinergic receptors, gluta- gastrointestinal motor activity (36, 38). minergic NMDA receptors, vanilloid and somato- The modulating influence of the brain-gut axis statin ones belong to this group. Purinergic recep- was also found as the next pharmacological target tors P2X take part in generating the visceral pain. It point. The activation of the HPA axis by compre- was shown, that P2X antagonists were effective in hended wide stress factors contributes to the devel- reducing the visceral pain in the course of the opment of dyspeptic disorders. The HPA hyperac- inflammatory reaction in the animal model. The tivity was discovered in the FGIDs course what was similar effect was observed after the NMDA antag- associated with the raised proinflammatory cytokin onists, although dextromethorphan paradoxically level. Thus, the corticotropin (CRF) receptor antag- caused an increase of nociception in the response to onists make up the next alternative of the functional the colon expansion. Vanilloid receptors are situat- diseases treatment, especially these ones occuring as ed on the afferent endings, stimulated by capsaicin, a result of the excessive reaction on numerous envi- pH fall and the temperature change. They particu- ronmental stressors (36, 38). larly occur in the stomach antrum, playing the sup- The present research studies are also concen- pressive role in gastric nociception. Thus, vanilloid trated on new prokinetic agents discovery. They receptor agonists may become an important phar- would broaden the arsenal of medicines applied macological agents, administrated to diminish vis- mostly in PDS. The investigations aimed to motilin ceral pain. Somatostatin is the peptide modulating receptors agonists are of the the special attention. both the motility and secretion in the gastrointesti- The prokinetic effect of erythromycin is known nal tract. Somatostatin analogues (Octreotid) since many years, because gastric emptying acceler- showed profitable effects connected with the reduc- ation during the erythromycin treatment was tion of the postprandial fullness feeling in PDS observed. The new erythromycin analouges patients (36, 38). (ABT229) also show the prokinetic effect. Other The next interesting future pharmacological medicines working via different mechanisms ñ espe- target points in the FD treatment are cholecystokinin cially through the influence on dopaminergic and (CCK), tachykinin (NK) and corticoliberin (CRF) serotoninergic neurotransmition are studied. Itoprid receptors. Cholecystokinin is a neuropeptide is dopaminergic D2 receptor antagonist which also released in the gastrointestinal tract mostly in the reveals the properties of acetylcholinoesterase response to fatty meal. It is considered that CCK inhibitor. It has antiemetic and gastric emptying causes the strong inhibitory effect on gastric empty- acceleration properties. Sulpiride derivative, levo- Pathophysiological concepts of functional dyspepsia and irritable... 459

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