Lower GI Pharmacology 2024 PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn LOWER GASTROINTESTINAL TRACT PHARMACOLOGY Class Year 2 Course Gastrointestinal & Hepatology Lecturer Prof Will F...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn LOWER GASTROINTESTINAL TRACT PHARMACOLOGY Class Year 2 Course Gastrointestinal & Hepatology Lecturer Prof Will Ford Date Sept 2023  Pharmacology of lower GI tract disorders Inflammatory bowel disease (IBD) – Crohn’s disease – Ulcerative colitis Constipation Diarrhoea  Learning outcomes Describe the pathophysiology and pharmacology of inflammatory bowel disease Explain the mechanism of action and adverse effects of aminosalicylates, corticosteroids, immunosuppressive agents, antimicrobials and TNFα inhibitors Describe the pathophysiology and pharmacology of constipation and laxatives Explain the mechanism of action and adverse effects of dietary fibre/bulk- forming laxatives, osmotic laxatives and contact/stimulant laxatives Describe the pathophysiology and pharmacology of diarrhea and antidiarrheal agents Explain the mechanism of action and adverse effects of oral rehydration/electrolyte balance, anti-infective agents, absorbent agents and opioid derivatives  Inflammatory bowel disease Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions of the intestine – associated with mucosal immune activation and inflammation Crohn’s disease Ulcerative colitis Collagenous colitis Lymphocytic colitis Ischaemic colitis Diversion colitis Infective colitis Indeterminate colitis Note: IBD should not be confused with IBS (irritable bowel syndrome) which is a distinct and less severe condition – associated with altered motility and fluid transport  IBD – Crohn’s and UC Three major differences: 1) Site of inflammation CD - Anywhere UC - Colon and rectum 2) Occurrence of lesions CD – patchy (skip lesions) UC - continuous 3) Depth of Inflammation CD - transmural inflammation UC - mucosal inflammation only IBD – symptoms and consequences Abdominal pain Diarrhoea Rectal bleeding (more common in UC) Weight loss Anaemia (most prevalent extraintestinal symptom) Decreased quality of life - chronic fatigue - anxiety - depression - social withdrawal Increased susceptibility to cancer  Mechanisms of IBD Cytokines are central to inflammatory response Levels increased in IBD Movement of leukocytes into tissues Macrophages, mast cells and Th1 cells secrete TNFα TNFα stimulates macrophages to produce cytotoxic metabolites, increasing phagocytic activity – destroying tissue. Initiating Factors: Genetic susceptibility, diet, stress  Pathogenesis of IBD - Summary CD and UC affect ~ 1:200* of the population and have a complex, multifactorial, pathogenesis - Genetic Susceptibility - Environmental Factors - Altered microbiome (dysbiosis) - Epithelial dysfunction (loss of transport and barrier function) - Chronic immune activation Mucosal Inflammation  Drug treatment of IBD CD and UC are chronic diseases - there is currently no cure Therapy aims to: – induce remission – maintain remission – Enhance QoL Drugs used include: I. Aminosalicylates II. Antimicrobials Severity III. Steroids IV. Immunosuppressants V. Biologics Treatment of IBD - aminosalicylates Contain 5-aminosalicylic acid (5-ASA, mesalamine) Usually, the first treatment option for mild-to-moderate UC and CD Effective in preventing relapses and maintaining remission Given either orally or rectally Mechanism of action: Not fully understood Inhibit production of proinflammatory mediators in the mucosa including: – Prostaglandins & leukotrienes – Platelet-activating factor – Cytokines (e.g., TNFα) – Reactive oxygen species Treatment of IBD - aminosalicylates 5-ASA (mesalazine) is an intestine-specific form of aspirin Readily absorbed from the GI tract – Good when used as a suppository or enema – Bad when used orally – little active drug reaches the colon Various formulations enhance delivery to the distal intestine – Sulfasalazine – 5-ASA linked to sulfapyridine - metabolised by colonic bacteria to give free 5-ASA – Newer strategies for intestinal delivery include: – Pentasa, Asacol: 5-ASA with pH-  Treatment of IBD - antibiotics Luminal bacteria have important role in pathogenesis of IBD ­ Loss of epithelial barrier allows bacteria to access the mucosa Treatment influences IBD by several mechanisms – Altering the makeup of the intestinal microbiota to favour beneficial bacteria – Decreasing bacterial tissue invasion and treating micro-abscesses and fistula – Decreasing bacterial translocation and systemic dissemination Most commonly used: metronidazole and ciprofloxacin More useful in CD than UC and not useful in flare-ups or for Treatment of IBD - glucocorticoids Introduced as therapy for IBD in the 1950s Powerful, fast-acting anti-inflammatory drugs which are the mainstay of treatment for acute flare-ups – i.e., they are used to induce remission – effective in 90% of UC patients and 60-90% of CD patients long-term use is not advised because of undesirable side effects – rarely used for maintenance therapy e.g., prednisolone, methylprednisolone, hydrocortisone, budesonide Molecular mechanism of corticosteroids  From FFP1 Year 1 Treatment of IBD - glucocorticoids Annexin-1 MAPK phosphatase 1 Corticotropin-releasing hormone IL-1β Cytokines Cytokine receptors Collagenases Cytokines Cytokine receptors Collagenases COX-2 Treatment of IBD - glucocorticoids Side-effects limit use as maintenance therapy Cushing’s syndrome: fat deposition, dysphoria, hypertension, hyperglycaemia, acne, bruising, hirsuitism Irreversible loss of bone density (osteoporosis) Recommended: Short pulses of treatment to induce remission, with dose tapering Maintain remission with mesalazine Treatment of IBD - immunosuppressants Used when steroids and 5-ASA fail to control inflammation Purine analogues inhibit nucleic acid synthesis for long-term maintenance of UC and CD – Mercaptopurine (6-MP), azathioprine (mercaptopurine prodrug) – Inhibit the proliferation of T and B lymphocytes – Slow onset of therapeutic effect (months) Treatment of IBD - immunosuppressants Used when steroids and 5-ASA fail to control inflammation Methotrexate – Usually prescribed to patients who haven’t responded to other medications (such as azathioprine) – Doses 100-fold less than used in oncology – Inhibits dihydrofolate reductase and synthesis of purine nucleotides Interferes with DNA synthesis and cellular replication – Also inhibits AICAR transformylase Increases circulating adenosine  Treatment of IBD - biologics For severe UC and Crohn’s Infliximab binds to soluble and transmembrane TNF – Prevents TNF from binding to its receptors – First biologic approved for use in IBD Adalimumab, Golimumab – humanised anti-TNF Ab Etanercept – decoy receptor, binds TNF Side effects and costs limit use – bone marrow suppression, hepatic fibrosis, opportunistic infections  Treatment of IBD - Other Faecal transplantation (FMT) – Dysbiosis may cause/contribute to intestinal inflammation – Alter microbial biome by transplanting biota from healthy donor Systematic reviews of clinical evidence – [UC and CD] Imdad et al. Fecal transplantation for treatment of inflammatory bowel disease. Cochrane Database of Systematic Reviews 2023, Issue 4. Art. No.: CD012774. DOI: 10.1002/14651858.CD012774.pub3 – Insufficient evidence of efficacy – [IBS] Halkjær et al. Fecal microbiota transplantation for the treatment of irritable bowel syndrome: A systematic review and meta-analysis. World J Gastroenterol. 2023 May 28;29(20):3185-3202. doi: 10.3748/wjg.v29.i20.3185. PMID: 37346153; PMCID: PMC10280798. – Insufficient evidence of efficacy Drugs used to treat diarrhoea and constipation  Diarrhoea An illness that causes you to pass waste from your body very frequently and in liquid rather than solid form ≥ 3 loose or liquid stools per day for 3 days acute (14 days) Constipation The condition of being unable to easily pass waste from your body < 3 bowel movements a week associated with hard lumpy stools and straining  The ideal poop Developed at the University of Bristol in 1997 Used as a clinical communication aid and as a research tool to evaluate the effectiveness of treatments for various diseases of the bowel  Causes of constipation Usually, occurs when peristaltic action is diminished – Stool moves too slowly and becomes hard and dry Diet: Insufficient intake of dietary fibre, insufficient H20 intake Iatrogenic: caused by medication (e.g. diuretics, opioids) Obstructions: Strictures, tumours Neurological/hormonal conditions – e.g., hypothyroidism, multiple sclerosis, Parkinson’s disease Psychosomatic constipation – based on anxiety (e.g., new job, exams) Irritable Bowel Syndrome: 1/3 of IBS patients have IBS-C Treatment – lifestyle management Most commonly constipation is due to poor lifestyle/diet and responds to appropriate changes: Increase fluid (drink more water) Increase fibre (vegetables, fruit, wheat, bran etc.) Increase exercise (minimum weekly) Regular bowel habit (same time every day) If no improvement can use laxatives  Laxatives Drugs which promote defaecation – Laxative: elimination of soft, formed stool – (Cathartic: copious, fluid evacuation) Main characteristics of laxatives – Retain water and electrolytes in lumen via hydrophilic/osmotic properties:  transit via  bulk –  Mucosal absorption of H2O and  Bulk-forming laxatives Fibre: (e.g., methylcellulose, psyllium, bran) Undigestible carbohydrates (found in fruit, wheat, leafy veg) Causes H2O to be retained in the intestine and softens stool Adds bulk to the stool and promotes peristalsis Gentlest on the body and safest to use (and should be 1st choice) Side effects include excessive gas (can be reduced by gradually increasing the dose) Risk of faecal impaction - always ensure plentiful water intake Takes time to have effect (weeks) Drug interactions: Decreased absorption of digoxin, warfarin, and salicylates if taken within 2hrs of these laxatives  Osmotic laxatives Retained in bowel, hold water in lumen via osmotic properties Require 1-2 days to work Can be given as an enema – more rapid effect (20 mins) Must administer with water to prevent dehydration Use should be monitored carefully as can cause cramps, electrolyte disturbances, and severe diarrhoea – Extra care in children and with renal impairment – e.g., lactulose (Dulax), polyethelene glycol (MoviCol), sodium phosphate (Fleet Enema), magnesium hydroxide (milk of magnesia)  Stimulant laxatives Senna (Senokot) – derived from the Senna plant ­ active component is anthracenes (sennosides) Bisacodyl (Duco-Lax) – drug used since 1953 Mechanism of Action ­ Stimulate enteric nervous system ↑ peristalsis ­ Take 8-10 hrs to work when taken PO – Take at night ­ Work faster if given as a suppository (1-2 hrs) or enema (5-20 min) Side effects – bloating, cramping and diarrhoea Warning: ­ Considered the harshest of laxatives and should not be used regularly ­ Can cause laxative dependency by disrupting the body's natural ability to defaecate Must be vigilant for laxative abuse  Pregnancy Pregnant women predisposed to constipation - ↑ progesterone, ↓ motilin levels, ↑ water absorption, ↓ maternal activity, ↑ consumption of mineral/vitamin supplements - Later in pregnancy, enlarged uterus. - 2nd most common GI complaint for pregnant women 1st line treatment (life-style changes) ­ ↑ Dietary fibre, ↑ fluid intake, ↑ exercise 2nd line treatment: laxatives ­ Very little systemic absorption – no apparent risk for foetus ­ Avoid use of osmotic or stimulant other than for short-term use due risk of dehydration and electrolyte imbalance.  Summary Constipation is very common Occurs primarily due to slow intestinal motility Consider if it may be due to adverse drug effects Treat 1st with lifestyle changes (diet, H2O and exercise) ­ Subsequently with bulk-forming laxative ­ osmotic laxatives ­ stimulant laxatives Seek further tests if constipation persists with laxative treatment ­ could be a warning sign of a more serious problem ­ e.g., colon cancer, diabetes, or hypothyroidism, among others Be alert about laxative abuse ­ most commonly abused are stimulant laxatives  Types of diarrhoea Acute – Infections Enterotoxins (e.g., E. coli, V. cholerae, Shigella, Salmonella) Rotavirus, Norwalk virus Parasites (e.g., Giardia, Entamoeba) – Dietary Spicy, sugary or fatty food Alcohol Caffeine Chronic – Motility-related, e.g., IBS – Inflammatory, e.g., IBD – Osmotic, e.g., lactose, gluten – Secretory, e.g., allergies – Many others (deficiencies, autoimmune)  Treatment of diarrhoea Main approaches: Treat the symptoms – Oral rehydration – NaCl and glucose for infant diarrhoea Treat the causes – Avoidance (e.g., food allergies, lactose intolerance) – Drug therapy - Anti-diarrhoeals - Antibiotics - Absorbant agents - Anti-inflammatories  Treatment for diarrhoea - ORT Maintaining hydration is first priority in the treatment of any diarrhoea Use Oral Rehydration Therapy Mechanism ORT primarily contains salts and glucose Acts by driving Na+ and glucose absorption in the small intestine via the Na+/glucose co-transporter (SGLT-1) & water follows by osmosis Restores electrolyte balance and drives fluid absorption Does not cure/prevent/reduce diarrhoea Maintains hydration while the diarrhoea expels the pathogen from the intestine Preparation (Sachets) The contents of each sachet should be dissolved in fresh drinking water and used immediately  Treatment for diarrhoea - opiates Work by slowing intestinal transit ­ Enables more fluid to be absorbed ­ e.g., loperamide; sold as Imodium Mechanism of Action Mu (μ) opiate receptor agonists decrease the activity of the myenteric plexus ­ Reduces peristaltic activity and allows more time for water to be absorbed from stool Should not be taken if there is blood or mucus in the stool and/or there is high fever ­ Indicative of severe infections (diarrhoea is beneficial) Should not be given to children < 3 (paralytic ileus) Not recommended in pregnancy or with breastfeeding  Treatment for diarrhoea - opiates Pharmacokinetics Loperamide comes as a tablet, capsule, liquid, or immediate release ­ Take 2 tablets (4 mg) immediately and then 1 tablet (2mg) after each bowel movement ­ Peak plasma levels = 4-5 hrs; Half-life of 10-11 hours ­ Use in combination with ORT to prevent dehydration Adverse effects Mild: Constipation, drowsiness, mild abdominal bloating and cramps, dry mouth, fatigue Serious: Allergic reactions ­ Hives, difficulty breathing, swelling of face, lips, tongue, or throat ­ discontinue use and seek emergency medical attention Treatment for diarrhoea - antibiotics Used for treating infectious diarrhoea ­ Both acute and chronic Bacteria – e.g., E. coli, Salmonella, Campylobacter, C. difficile (e.g., rifaximin, ciprofloxacin, azithromycin) Viruses – e.g., rotavirus, coronavirus, norovirus ­ No drugs – Only ORT until symptoms subside Parasites – e.g., giardia, amoeba ­ (e.g., metronidazole (Flagyl), tinidazole) Use of antibiotics should be limited Antibiotics may be recommended if you have severe diarrhoea and a specific type of bacteria has been identified as the cause – Not recommended if the cause is unknown Treatment for diarrhoea – adsorbents Act by binding to luminal toxins ­ Prevents entry into the body ­ Enhances elimination Examples include: ­ Kaolin - aluminium clay ­ Pectin – fibre derived from citrus fruit ­ Activated charcoal ­ Bismuth subsalicylate (Pepto-Bismol) Side effects are rare but possible ­ Drug interactions must be considered  Further reading Malfertheiner P, Chan FCL, McColl KEL. Peptic ulcer disease. Lancet 2009; 374: 1449-61 Giulia, R., Siew, C. N., Kotze, P. G., Marjorie, A., Remo, P., Antonino, S.,... Silvio, D. (2020). Crohn’s disease (primer). Nature Reviews: Disease Primers, 6(1) doi:https://doi.org/10.1038/s41572-020-0156-2 Gisbert JP, Chaparro M. Common Mistakes in Managing Patients with Inflammatory Bowel Disease. Journal of Clinical Medicine. 2024; 13(16):4795. https://doi.org/10.3390/jcm13164795 Ordas I et al. Ulcerative colitis. Lancet 2012; 380: 1606-1619 Sharkey KA & McNaughton WK. Gastrointestinal Motility and Water Flux, Emesis, and Biliary and Pancreatic Disease. Chapter 54. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th edition (Eds. Brunton LL et al). McGraw-Hill, New York, 2023