Updates in Irritable bowel Syndrome management.pptx

Updates in Irritable bowel Syndrome management, updated drugs and etc..

1. UPDATES IN IBS management Omer Muhammed Msc . Candidate in pharmacology Hawler medical University

2. outlines Definition PHYSICAL FINDINGS & CLINICAL PRESENTATION EPIDEMIOLOGY & DEMOGRAPHICS ETIOLOGY Role of SEROTONIN IN GIT Role of Mast cells in GIT Conventional TREATMENTs Dietary Interventions Updates in IBS-C treatments Updates in IBS-D treatments NOVEL IBS DRUGS (in clinical trials)

3. Definition Irritable bowel syndrome  (IBS) is a chronic functional disorder manifested by alteration in  bowel habits  and recurrent abdominal pain and bloating. SYNONYMS: Irritable colon Spastic colon IBS Types: Mostly diarrhea and abdominal discomfort ( IBS-D ). Mostly constipation and abdominal discomfort ( IBS-C ). Alternating loose stools and constipation with abdominal discomfort ( IBS-mixed ). Undefined subtype ( IBS-U )  symptoms vary.

4. EPIDEMIOLOGY & DEMOGRAPHICS IBS occurs in 20% of population of industrialized countries and is responsible for >50% of GI referrals. Worldwide adult prevalence is 12%. •Female: male ratio is 2:1. •Nearly 50% of patients have psychiatric abnormalities, with anxiety disorders being most common. *Epidemiological features of IBS and its subtypes among Iranian adults from Hassanzadeh Keshteli et al., 2015

5. PHYSICAL FINDINGS & CLINICAL PRESENTATION The clinical presentation of IBS consists of abdominal pain and abnormalities of defecation, which may include  loose stools  usually after meals and in the morning, alternating with episodes of constipation. •Physical examination is generally normal. •Nonspecific  abdominal tenderness  and distention may be present.

6. ETIOLOGY Unknown •Associated  pathophysiology  includes altered GI motility and increased gut sensitivity •Risk factors: anxiety, depression, personality disorders.

7. Role of SEROTONIN IN GIT Neuroendocrine signaling molecule serotonin (5-HT) regulates gut motility, intestinal transit, secretion, and visceral nociception. Increased mucosal 5-HT is linked to diarrhea and abdominal pain in diarrhea-predominant irritable bowel syndrome (IBS-D). IBS-D patients have elevated postprandial serotonin levels, which correlate with abdominal pain and diarrhea. 5-HT induce pain by activating afferent fibers 5-HT binds to receptors (on immune cells, such as mast cells and macrophages)  induces mucosal inflammation

8. Serotonin levels Normally:  5-HT is taken up by serotonin reuptake transport (SERT) and degraded by monoamine oxidase (MAO) into 5-hydroxyindole acetic acid (5-HIAA) in the cells to optimize the luminal 5-HT level. In patients with IBS-D :  decreased transcription of SERT resulting in elevated serotonin level  causing discomfort. In patients with IBS-C :  low levels of TPH and high levels of SERT decreased serotonin discomfort

9. Role of Mast cells in GIT Mast cells are important in mediating numerous abnormal gastrointestinal physiologic processes that precipitate gastrointestinal disorders such as IBS. Gut mast cells infiltrate the intestine and colon tissues near injury sites, including the mucosal barrier. Interestingly, mast cell stabilizers, such as cromolyn sodium, have been shown to reverse visceral hypersensitivity and improve symptoms in patients with IBS.

10. LOW GRDAE INFLAMMATION  due to: impaired epithelial barrier, dysbiosis and altered stress levels a consequence of past history or history of PI-IBS (post-infectious IBS) Leads to increased number of immune cells : mast cells (especially near enteric nerve fibers in gut mucosa of IBS patients) lymphocytes   cytokine production in peripheral blood mononuclear cells (PBMCs) and intestinal mucosa  dysbiosis : increased levels of C-reactive protein, IL-6, and IL-8

11. DIAGNOSIS DIFFERENTIAL DIAGNOSIS • IBD •Colon  malignancy •PUD •Biliary liver disease • Chronic pancreatitis The criteria for diagnosis of IBS are: more than 3 months of symptoms including abdominal pain that is relieved by a bowel movement, or pain accompanied by a change in bowel pattern, and abnormality in bowel movement 25% of the time, characterized by two of the following features: Abdominal distention Abnormal consistency Abnormal defecation (e.g., straining, sense of incomplete evacuation) Abnormal frequency Mucus  with bowel movement REFERRAL: Greater than 60% of patients respond successfully to treatment over the initial 12 mo ; however, IBS is a chronic relapsing condition and requires prolonged therapy. referral is recommended in patients with rectal bleeding, fever, nocturnal diarrhea, anemia, weight loss, or onset of symptoms after age 40 yr.

12. TREATMENT Treatment options for IBS according to predominant symptoms and their severity. (Ferreira et al., 2019)

13. Conventional TREATMENTs / NONPHARMACOLOGIC THERAPY The patient should be encouraged to maintain a high-fiber diet and to eliminate foods that aggravate symptoms. Avoidance of dietary caffeine and dietary excesses is also helpful. •Behavioral therapy is also recommended because psychosocial stressors are important triggers of IBS. •Importance of regular exercise and adequate fluid intake should be stressed.

14. Conventional TREATMENTs / GENERAL Rx The mainstay of treatment of IBS is high-fiber diet. Because symptoms are chronic, the use of laxatives should be avoided. •Fiber supplementation with  psyllium  1 to 2 tablespoons bid followed by 8 oz of water may be necessary in some patients. •Patients should be instructed that there might be some increased bloating on initiation of fiber supplementation, which should resolve within 2 to 3 wk. It is important that patients take these fiber products on a regular basis and not only  prn . Slow  titration  may help. Antispasmodics-anticholinergics may be useful in refractory cases (e.g.,  dicyclomine  [ Bentyl ] 10 to 20 mg up to three times daily). •Patients who appear anxious can benefit from use of sedatives and  anticholinergics  such as chlordiazepoxide- clidinium ( Librax ) or  SSRIs .

15. pharmacological therapies for IBS based on predominant symptoms, with dosage and level of evidence (Ferreira et al., 2019)

16. Updates in IBS treatment Recent scientific studies have explored various treatments for Irritable Bowel Syndrome (IBS), focusing on dietary interventions, psychological therapies, and the use of probiotics.

17. Dietary Interventions A randomized controlled trial compared the efficacy of a low-FODMAP diet, a low-carbohydrate diet, and optimized medical treatment in reducing IBS symptom severity. After four weeks, 76% of participants on the low-FODMAP diet and 71% on the low-carbohydrate diet experienced significant symptom reduction, compared to 58% in the medical treatment group. These findings suggest that dietary interventions may be more effective than pharmacotherapy in managing IBS symptoms. A low-FODMAP diet involves reducing the intake of certain carbohydrates known as FODMAPs—Fermentable Oligo-, Di-, Mono-saccharides, and Polyols—that are poorly absorbed in the small intestine and can cause digestive discomfort.

18. Dietary Interventions High-FODMAP Foods to Avoid Foods high in FODMAPs include certain fruits like apples and pears, vegetables such as onions and garlic, legumes, dairy products containing lactose, and sweeteners like sorbitol.  Low-FODMAP Alternatives Alternatives include fruits like oranges and grapes, vegetables such as carrots and cucumbers, lactose-free dairy products, and gluten-free grains.

19. Psychological Therapies Cognitive behavioral therapy (CBT) is an effective brain-targeted intervention that teaches information processing skills to address psychological factors known to exacerbate abdominal symptoms including maladaptive coping, intense worry (e.g., catastrophizing, prediction error), stress reactivity, and hypervigilance to threat cues.

20. Psychological Therapies Research indicates that cognitive behavioral therapy (CBT) can modulate the brain-gut-microbiome axis, leading to symptom relief in IBS patients. A study demonstrated that behavioral self-management through CBT induced changes in brain function and the gut microbiome, highlighting its potential as a non-drug treatment option. Jacobs, et al. "Cognitive Behavioral Therapy for Irritable Bowel Syndrome Induces Bidirectional Alterations in the Brain-Gut-Microbiome Axis Associated with Gastrointestinal Symptom Improvement." Microbiome (2021)

21. A substantial body of evidence indicates alterations in anatomical and functional connectivity within brain networks of IBS patients, associated with emotional arousal, salience evaluation, sensorimotor processes, and brainstem functionality. (Jacobs et al., 2021)

22. Probiotics Specific probiotic strains have shown promise in managing IBS symptoms. For instance, Lactobacillus acidophilus NCFM may help alleviate abdominal pain, while Saccharomyces boulardii might benefit individuals with diarrhea-predominant IBS. For 15 days, people in the study received either diet advice or Saccharomyces boulardii  and diet advice.  Diarrhea  and other symptoms improved for both groups. However, those who took this strain of probiotic showed more improvement. (D’Souza et al., 2017)

23. Updates in IBS-C treatments 1. Targeting guanylyl cyclase C Guanylyl cyclase C (GC-C) is an enzyme that reglulates secretion in the intestines GC-C activation by guanylin (GN) and uroguanylin (UGN)  catalyzes the synthesis of cGMP in response to a meal  of intracellular cGMP  activates cGMP protein kinase  phosphorylation of downstream targets, including the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel CFTR activation   secretion of chloride and bicarbonate ions into the intestinal lumen  followed by water culminating   intestinal fluid secretion and accelerated GI transit.

24. Updates in IBS-C treatments 1. Targeting guanylyl cyclase C A. Linaclotide ( Constella , Linzess ) synthetic analog of GN and UGN Dual MOA: Act as GC-C agonist (LAXATIVE) and modulate colonic nociceptors (ANALGESIC) by reducing visceral hypersensitivity. B. Plecanatide is a synthetic analog of uroguanylin , MOA similar to that of linaclotide S.E: The most bothersome adverse effect was diarrhea; it led to discontinuation in 5% of linaclotide-receiving patients

25. Updates in IBS-C treatments 1. Targeting guanylyl cyclase C Linaclotide is a selective guanylate cyclase-C (GC-C) agonist that regulates intestinal fluid balance and motility. Its dual mechanism involves stimulating GC-C to increase cyclic guanosine monophosphate (cGMP) levels, activating the CFTR ion channel, which enhances chloride and bicarbonate secretion while inhibiting sodium absorption, accelerating gastrointestinal transit. Additionally, elevated extracellular cGMP reduces visceral hypersensitivity by inhibiting colonic nociceptors, alleviating intestinal pain. (Layer and Stanghellini , 2014)

26. Updates in IBS-C treatments 2. Prostaglandin derivative (Lubiprostone) Lubiprostone ( Amitiza ) belongs to the family of bicyclic fatty acid prostaglandins E1 and activates chloride channel type 2  causing an efflux of chloride into the intestinal lumen. Lubiprostone is approved by FDA) and in Europe for treating chronic constipation and C-IBS. Adults—24 micrograms (mcg) two times a day with food and water. SE: Diarrhea, Full or bloated feeling, Swelling of the abdominal or stomach area

27. Updates in IBS-C treatments 3. Sodium-hydrogen exchanger inhibitor (Tenapanor) NHE3 facilitates the absorption of sodium and phosphate in the gastrointestinal tract. MOA: NHE3 inhibition:  reduces sodium absorption   sodium concentration in the gut   secretion of fluids  improves the function of tight junctions in the small intestine and enhances transepithelial electrical resistance   visceral hypersensitivity through its antinociceptive effects. DOSE: 50 mg PO BID immediately before breakfast and dinner S.E: Diarrhea was the most common adverse effect

28. Updates in IBS-C treatments 4. partial agonist of the 5-HT4 receptor  5-HT is directly involved in:  initiating the peristaltic reflex,  in facilitating intraluminal secretions Tegaserod (zelnom) is a partial agonist of the 5-HT4 r (5-HT42B) receptor that stimulates peristaltic gastrointestinal reflexes and intestinal secretion, inhibiting visceral sensitivity, enhancing basal motor activity. initial dose: 6 mg orally twice a day before meals for 4 to 6 weeks Originally approved in 2002  withdrawn due to increased ischemic cardiovascular events   reapproved with box of warning in 2019 Discontinued in United States June 30, 2022: Manufacturer withdraws drug from market for a second time and will no longer make the product available in the US marketplace

29. Updates in IBS-D treatments 1. Inhibition of serotonergic pathway (alosetron, cilansetron) activation of 5-HT3 receptors (on intrinsic primary afferent neurons with submucosal terminals)  initiates the peristaltic reflex and modulates intestinal secretion MOA: slow colonic transit Reduce gastrocolonic reflex, rectal sensitivity ,and postprandial motility ALOSTERON: Dose: Initial 0.5 mg PO q12hr for 4 weeks; if well tolerated, but inadequate control of IBS symptoms, increase up to 1 mg q12hr; discontinue if no improvement after 4 weeks The drug was reintroduced in 2002 with a black box warning for ischemic colitis, and its use is limited to women with severe IBS-D after failure of conventional therapies.

30. 2. Targeting opioid receptors (Loperamide, eluxadoline) μ- (MOP) receptors  control motility δ- (DOP) receptors  secretion. Opioid receptor agonists slow GI and colonic transit, increase fluid absorption and reduce pain sensation A. Loperamide: a peripherally restricted agonist of MOP receptors usual dose is 4 mg (2 tablets) after the first loose bowel movement, and 2 mg (1 tablet) after each loose bowel movement. B. Eluxadoline This agent is a mixed mu- and kappa-opioid receptor agonist that reduces gastric peristalsis and delays transit time. Usual dose: 100 mg orally twice a day

31. 3. Targeting gut microbiota, mucosal inflammation, and microbiota stabilization. (antibiotics)  Antibiotic (rifaximin) Rifaximin is a non-systemic antibiotic with very low bioavailability that presents anti-inflammatory activity. MOA: Current studies indicate that rifaximin induces only modest effects on the gut microbiota of patients with IBS-D, suggesting that the efficacy of rifaximin may involve other mechanisms. Indeed, preclinical data reveal a potential role for rifaximin in the modulation of inflammatory cytokines and intestinal permeability . (Chey et al., 2020) Dose: 200 mg PO q8hr for 3 days *FDA approved for IBS-D as a short-term course (14 days) that may be repeated up to two times

32. NOVEL IBS DRUGS (in clinical trials) Renzapride Renzapride is a prokinetic agent that functions as a full agonist at 5-HT₄ receptors and a partial antagonist at 5-HT₃ receptors. Initially developed for IBS with constipation (IBS-C), renzapride has undergone various clinical evaluations. In 2024, Ambrose Healthcare acquired renzapride, focusing on its potential to manage gastrointestinal motility issues in patients with cystic fibrosis. Phase 2 clinical study assessing Renzapride in Constipation Predominant Irritable Bowel Syndrome (IBS-c)

33. NOVEL IBS DRUGS (in clinical trials) Olorinab Olorinab is a selective agonist of the cannabinoid receptor type 2 (CB₂), developed by Arena Pharmaceuticals. It is designed to manage gastrointestinal pain associated with conditions like Crohn’s disease and IBS. By targeting CB₂ receptors, olorinab aims to reduce visceral hypersensitivity without central nervous system side effects.

34. NOVEL IBS DRUGS (in clinical trials)  a phase 2b, randomized, double-blind, placebo-controlled, parallel-group trial. Eligible participants aged 18-70 years with IBS-C and IBS-D diagnosed per Rome IV received olorinab 10 mg, 25 mg, or 50 mg three times daily (TID) or placebo TID for 12 weeks. The primary endpoint was the change in patient-reported average abdominal pain score (AAPS) from baseline to Week 12. (Chang et al., 2023)

35. Opioid delta-receptor agonists/ KNT-127 The research published in the  British Journal of Pharmacology  on December 25, 2024, discovered that a class of drugs called opioid delta-receptor (DOP) agonists may help alleviate IBS symptoms by targeting the central nervous system rather than acting directly on the intestine. A relatively new agonist of δ -receptors, KNT-127, exhibits high selectivity and agonistic activity toward δ -receptors compared with the prototypic δ -receptor agonists and potentially acts as a biased ligand that mainly activates  cAMP   signalling with lower activation of β- arrestin signalling . KNT-127 exerts antidepressant-like effects at an earlier stage than conventional antidepressants, such as (SSRIs). (Yoshioka et al., 2025)

36. References IBS: A comprehensive overview of irritable bowel syndrome . (n.d.). ScienceDirect. https://www.sciencedirect.com/book/9780128213247/a-comprehensive-overview-of-irritable-bowel-syndrome Corsetti M, Whorwell P. Novel pharmacological therapies for irritable bowel syndrome.  Expert Rev Gastroenterol Hepatol . 2016;10(7):807-815. doi:10.1586/17474124.2016.1158099 Lacy BE. Update on Irritable Bowel Syndrome Guidelines.  Gastroenterol Hepatol (N Y) . 2020;16(12):648-650. Hung TH, Wang CY, Lee HF. Update in diagnosis and management of irritable bowel syndrome.  Tzu Chi Med J . 2023;35(4):306-311. Published 2023 Sep 22. doi:10.4103/tcmj.tcmj_104_23 Corsetti M, Whorwell P. Novel pharmacological therapies for irritable bowel syndrome.  Expert Rev Gastroenterol Hepatol . 2016;10(7):807-815. doi:10.1586/17474124.2016.1158099 Mishima Y, Ishihara S. Enteric Microbiota-Mediated Serotonergic Signaling in Pathogenesis of Irritable Bowel Syndrome.  International Journal of Molecular Sciences . 2021; 22(19):10235. https://doi.org/10.3390/ijms221910235

37. References Chang, L. et al. (2023) ‘Efficacy and safety of olorinab , a full agonist of the cannabinoid receptor 2, for the treatment of abdominal pain in patients with irritable bowel syndrome: Results from a phase 2b randomized placebo-controlled trial (CAPTIVATE)’, Neurogastroenterology and Motility , 35(5), p. e14539. Available at: https:// doi.org /10.1111/nmo.14539. Chey, W.D., Shah, E.D. and DuPont, H.L. (2020) ‘Mechanism of action and therapeutic benefit of rifaximin in patients with irritable bowel syndrome: a narrative review’, Therapeutic Advances in Gastroenterology , 13, p. 1756284819897531. Available at: https:// doi.org /10.1177/1756284819897531. D’Souza, B. et al. (2017) ‘Randomized controlled trial of probiotics after colonoscopy’, ANZ Journal of Surgery , 87(9), pp. E65–E69. Available at: https:// doi.org /10.1111/ans.13225. Ferreira, A.I., Garrido, M. and Castro- Pocas , F. (2019) ‘Irritable Bowel Syndrome: News from an Old Disorder’, GE - Portuguese Journal of Gastroenterology , 27, pp. 1–14. Available at: https:// doi.org /10.1159/000503757. Hassanzadeh Keshteli , A. et al. (2015) ‘Epidemiological features of irritable bowel syndrome and its subtypes among Iranian adults’, Annals of gastroenterology : quarterly publication of the Hellenic Society of Gastroenterology , 28, pp. 253–258. Irritable Colon - an overview | ScienceDirect Topics (no date). Available at: https:// www.sciencedirect.com /topics/pharmacology-toxicology-and-pharmaceutical-science/irritable-colon (Accessed: 9 March 2025). Jacobs, J.P. et al. (2021) ‘Cognitive behavioral therapy for irritable bowel syndrome induces bidirectional alterations in the brain-gut-microbiome axis associated with gastrointestinal symptom improvement’, Microbiome , 9(1), p. 236. Available at: https:// doi.org /10.1186/s40168-021-01188-6. Layer, P. and Stanghellini , V. (2014) ‘Review article: linaclotide for the management of irritable bowel syndrome with constipation’, Alimentary Pharmacology & Therapeutics , 39(4), pp. 371–384. Available at: https:// doi.org /10.1111/apt.12604. Phase 2 clinical study assessing Renzapride in Constipation Predominant Irritable Bowel Syndrome (IBS-c) - AdisInsight (no date). Available at: https:// adisinsight.springer.com /trials/700380809 (Accessed: 12 March 2025). Review article: linaclotide for the management of irritable bowel syndrome with constipation (no date) PubMed Central (PMC) . Available at: https:// pmc.ncbi.nlm.nih.gov /articles/PMC4305214/ (Accessed: 11 March 2025). Yoshioka, T. et al. (2025) ‘Agonists of the opioid δ -receptor improve irritable bowel syndrome-like symptoms via the central nervous system’, British Journal of Pharmacology , 182(7), pp. 1599–1609. Available at: https:// doi.org /10.1111/bph.17428.

38. Thank you