GI Pharmacology

GI Pharmacology Johann Graggaber SpR Clinical Pharmacology Topics        Peptic ulcer disease/dyspepsia GORD Inflammatory bowel disease Irritable bowel syndrome Diarrhoea Constipation Pancreatitis Dyspepsia / Peptic ulcer disease Dyspepsia: upper abdo pain/discomfort (fullness, bloating, distension, nausea) Peptic ulcers defects in mucosa extending through muscularis mucosae Prevalence PUD 5-10% lifetime dyspepsia 25-40% Aetiology (most common)  H.pylori  NSAIDs Mucosa protective factors Parietal cell and acid regulation NSAIDs       Antiinflammatory Analgesic Antipyretic Chemically heterogeneous Reversible competitive inhibitors of COX activity (Aspirin irreversible) Reduce prostaglandin synthesis (COX-1)      ↓ Mucus ↓ bicarbonate ↓ blood flow ↓ proliferation of cells ↑ gastric acid secretion   Reduce production of superoxide radicals, induce apoptosis, inhibit expression of adhesion molecules, decrease NO synthase and proinflammatory cytokines, modify lymphocyte activity and alter cellular membrane functions Biliary excretion and reflux of metabolites into stomach Helicobacter pylori    Peptic ulcers Gastric carcinoma/lymphoma Mucosal atrophy Tests      Urea breath test (sens. and spec. ~95%) Endoscopic (urease, histology) Stool antigen (sens. and spec. ~ 95%) (serology) Omit PPI for 2 weeks prior to tests H. pylori Management of dyspepsia    Therapeutic trial of acid suppressing medication H. pylori screening If alarm features    Gastric ulcer     GI bleeding Unintentional weight loss Progressive dysphagia Odynophagia Persistant vomiting Iron deficiency anaemia Mass/ suspicious barium meal  Do Endoscopy Treatment Lifestyle advice   Diet (alcohol, caffeine…) Smoking Medication       Stop NSAIDs if possible H-2 receptor antagonists Proton pump inhibitors H. pylori eradication Antacids Misoprostol (NSAIDs) H2 receptor antagonists       Cimetidine, Ranitidine, Famotidine, Nizatidine Competitive and selective inhibition of histamine H-2 receptor Suppress 24 hr gastric secretion by 70% Less effective than PPI Caution: Interaction: renal failure, pregnancy, breast feeding Cimetidine binds to CYP 450 (retards oxidative drug metabolism) note interactions with warfarin, phenytoin, theophylline..  Side effects     Well tolerated, less than 3% adverse effects Diarrhoea, headache, drowsy, fatigue, constipation, CNS, LFT Rarely pancreatitis, bradycardia, AV block, confusion (elderly, especially cimetidine) Rarely blood dyscrasias Proton pump inhibitors  Omeprazole, Lansoprazole, Pantoprazole, Esomeprazole, Rabeprazole    Prodrugs activated in acidic secretory canaliculi Inhibit gastric H+K+ ATPase irreversibly Decrease acid secretion by up to 95% for up to 48 hours Use: Ulcers, GORD, Zollinger-Ellison Syndrome, reflux oesophagitis Side effects       Generally well tolerated mc Gastrointestinal, headache, headache dizziness Omeprazole – impotence, gynaecomastia May increase risk of GI infections (reduced acidity)  Note: pH > 6 necessary for platelet aggregation Give high dose PPI in active GI bleed (eg Omeprazole 8mg/hr for 72 hrs) H. pylori eradication    Eradication increases ulcer healing Reduces recurrence MALT, Ca (can lead to resolution) Triple therapy For 7 (14) days twice daily eg    full dose PPI + Amoxicillin + Clarithromycin/Metronidazole Effective in 80-85% Other Antacids     Mg and Al hydroxides May chelate other drugs (avoid concomitant administration of other drugs) Side effects: diarrhoea (Mg), constipation (Al) Milk alkali syndrome (alkalosis, renal insufficiency, hypercalcemia) Forms sticky polymer in acidic environment Inhibits hydrolysis of mucous proteins by pepsin 1 g bd to 1g qds SE: constipation, aluminium absorption (avoid in severe renal impairment due to risk of encephalopathy) Sucralfate     Misoprostol    PGE1 analogue Stimulates Gi pathway (↓cAMP and ↓gastric acid) ↑ blood flow and ↑ mucus and bicarbonate secretion Use: prevention of NSAID induced injury Side effects: diarrhoea, pain, cramps (30%) Can cause exacerbation of IBD Contraindication: pregnancy, caution in women of childbearing age can induce labour! Nonvariceal Upper GI Bleed    Resuscitate (iv access, fluids, catheter, transfusion) Bloods (cross match, FBC, U&E, clotting) Drugs    Acid suppressing drugs (stabilize clot) Somatostatin – reduces acid secretion and splanchnic blood flow Antifibrinolytic drugs – tranexamic acid reduces need for surgery and mortality   +/- transfuse Endoscopy: cause of bleeding, haemostasis (injection, clips, banding...), can usually wait until next day GORD Definition   Abnormal reflux of gastric contents into oesophagus ± mucosal damage Prevalence   > 50% of population > once a year 50% of patients have erosive oesophagitis Pathophysiology   Antireflux barrier (sphincter…) Acid, pepsin, trypsin, bile acids, hiatus hernia Symptoms     Heartburn Belching Asthma, cough Hoarseness, sore throat, globus Alarm features        GI bleeding Unintentional weight loss Progressive dysphagia Odynophagia Persistent vomiting Iron deficiency anaemia Mass/ suspicious barium meal Precipitants     Food (fatty food, alcohol, caffeine) Smoking Obesity Medication  calcium antagonists, nitrates, theophyllines, NSAIDs, corticosteroids  Pregnancy Usually chronic relapsing course Diagnosis   Symptoms Empirical therapy  Endoscopy    Failure of response to therapy Alarm features Barrett’s  24-hour pH monitoring   pH < 4 Limited sensitivity Complications    Oesophagitis Strictures, ulcers Barrett's Barrett's    Intestinal columnar metaplasia Malignant potential Needs surveillance Treatment Lifestyle advice      Dietary habits (fat, alcohol, caffeine, timing) Smoking Weight loss Raising head But little evidence for all those Medication     H-2 receptor antagonists PPI Antacids Prokinetics Inflammatory Bowel Disease Ulcerative colitis  Diffuse mucosal inflammation limited to the colon Crohn's disease   patchy transmural inflammation May affect any part of GI tract Features  UC  CD bloody diarrhoea, colicky pain, urgency, tenesmus abdominal pain, diarrhoea, weight loss intestinal obstruction systemic symptoms Drugs in IBD       Aminosalicylates Corticosteroids Thiopurines Methotrexate Ciclosporin Infliximab Aminosalicylates       Sulfasalazine (5-aminosalicylic acid and sulfapyridine as carrier substance) Mesalazine (5-ASA), eg Asacol, Pentasa Balsalazide (prodrug of 5-ASA) Olsalazine (5-ASA dimer cleaves in colon) Oral, rectal preparation Use Maintaining remission  Active disease  May reduce risk of colorectal cancer Adverse effects  10-45%  Nausea, headache, epigastric pain, diarrhoea, hypersensitivity, pancreatitis, blood disorders, lung disorders, myo/pericarditis  Caution in renal impairment, pregnancy, breast feeding   Corticosteroids    Antiinflammatory agents for moderate to severe relapses eg 40mg Prednisolone Inhibition of inflammatory pathways (↓IL transcription, suppression of arachidonic acid metabolism, lymphocyte apoptosis)  Side effects     Acne, moon face, oedema Sleep, mode disturbance Dyspepsia, glucose intolerance Cataracts, osteoporosis, myopathy… Thiopurines Azathioprine, mercaptopurine    Inhibit ribonucleotide synthesis Inducing T cell apoptosis by modulating cell signalling Azathioprine metabolised to mercaptopurine and 6-thioguanine nucleotides Use   Active and chronic disease Steroid sparing Leucopaenia (myelotoxic) Monitor for signs of infection, sore throat Flu like symptoms after 2 to 3 weeks, liver, pancreas toxicity Side effects    Methotrexate   Inhibits dihydrofolate reductase Probably inhibition of cytokine and eicosanoid synthesis Use  Relapsing or active CD refractory or intolerant to AZA or Mercaptopurine  Monitor FBC, LFT Side effects  GI  Hepatotoxicity, pneumonitis Ciclosporin Inhibitor of calcineurin, preventing clonal expansion of T cell subsets Use     Active and chronic disease Steroid sparing Bridging therapy Tremor, paraesthesiae, malaise, headache, abnormal LFT Gingival hyperplasia, hirsutism Major: renal impairment, infections, neurotoxicity Side effects    Monitor  Blood pressure, FBC, renal function Infliximab   Anti TNF-α monoclonal antibody Potent anti inflammatory effects Use  Fistulizing CD  Severe active CD refractory/intolerant of steroids or immunosuppression  iv infusion Side effects  Infusion reactions  Sepsis  Reactivation of Tb, increased risk of Tb Principles of Managment of IBD  Assess severity Mild and distal   topical steroids/aminosalicylates  Diffuse or not responding –  add oral steroids admit, iv steroids, iv fluids, ?TPN etc Avoid antimotility drugs and antispasmodics as may precipitate paralytic ileus and megacolon  Severe   Ulcerative colitis:  Medical management of UC Active left sided/extensive      Aminosalicylate eg Mesalazine Prednisolone 40mg (for prompt response or if mesalazine unsuccessful) – reduce dose gradually Azathioprine for steroid dependant disease Topical agents (rectal symptoms) Ciclosporin for severe, steroid refractory colitis Active distal UC   Mild/Mod topical mesalazine (or steroid) + oral mesalazine +/- oral steroids Severe UC    Admission for iv therapy Close monitoring  Daily physical examination, regular vital signs, stool chart, CRP, AXR  FBC, ESR, CRP, U&E, albumin, LFT every 24-48 hours  Daily AXR if colonic dilatation (transverse >5.5cm) Therapy  iv fluids and electrolytes if necessary  sc heparin (thromboembolism prophylaxis)  ? Nutritional support  iv steroids  Withdrawal of antidiarrhoeal agents (can precipitate dilatation)  Aminosalicylates  Topical therapy +/- surgical referral (colonic dilatation) Stool frequency (>8) and CRP (>45) on day 3 predict need for surgery Consider colectomy or iv ciclosporin Medical Management of CD  Assessment   Site, pattern (inflammation, stricturing, fistulating), prior disease activity Confirm disease activity (CRP, ESR) Mild – aminosalicylate Mod/severe – oral corticosteroids (reduce gradually over 8 weeks) Severe – iv steroids Elemental/polymeric diets TPN (fistulating) Azathioprine as steroid sparing agent Consider surgery Metronidazole +/- ciprofloxacin Azathioprine Infliximab  Active intestinal disease         Fistulating and perianal     Other sites Maintenance of remission of CD      STOP SMOKING Mesalazine of limited benefit Azathioprine effective but toxicity Methotrexate Infliximab Steroid refractory disease  Definition   Active disease on >20 mg prednisolone > 2 weeks Relapse when dose reduction   Azathioprine (monitor FBC) MTX, Infliximab Constipation   Stool: 70-85% water (100ml/d) Normal stool frequency ≥ 3/week Causes     Dietary (fibre), drugs, hormonal disturbances, neurogenic disorders systemic illnesses, IBS colonic motility disorder of defecation or evacuation (outlet) Management Diet, fluid, fibre rich diet  Avoidance of constipating drugs Only then consider medication (haemorrhoids, exacerbation of angina from straining…)  Laxatives      Bulk-forming Stimulant Faecal softeners Osmotic laxatives Bowel cleansing solutions   Oral Rectal-suppositories, enemas General Contraindications: intestinal perforation and obstruction Bulk-forming laxatives      Increase faecal mass which stimulates peristalsis Bulk/softness/hydration dependant on fibre Ensure adequate fluid intake (obstruction) Effect can be delayed by a few days Try dietary fibre first!   Wheat bran, oat bran, bran buiscuits Pectins/hemicellulose (fruits, vegetables)      Ispaghula (Fybogel, Isogel) Methylcellulose (Cevelac) Sterculia (Normacol) Contraindication: intestinal obstruction, colonic atony, faecal impaction Side effects: flatulence, abdominal distension, GI obstruction, rarely hypersensitivity Stimulant Laxatives  Increase intestinal motility Diphenylmethane derivatives  Sodium picosulfate, hydrolyzed by bacteria to active form, effects vary  Bisacodyl (Dulco-lax), usually 5-10mg nocte Anthraquinone Laxatives  Require activation in colon (bacteria), onset of action delayed (6-12 hours)  Senna (Senokot), plant derivative  Danthron (Co-danthramer) possibly carcinogenic, only use in terminally ill Docusate Sodium stimulant and softening Glycerol suppositories (Parasympathomimetics such as bethanechol, neostimin rarely used) Side effects: cramps, diarrhoea, hypokalaemia Osmotic laxatives Osmotically mediated water retention  Nondigestible sugars and alcohols     synthetic disaccharide, resists intestinal disacharidase draw water in osmotically, not absorbed Lactulose Use: elderly, opioids, hepatic encephalopathy (↓ ammonia production)    Magnesium salts Phosphates (rectal, Fleet) Sodium citrate (rectal, Micralax Micro-enema) Polyethylene Glycol-Electrolyte Solutions - Macrogels   Sequester fluid in bowel, poorly absorbed  Movicol Faecal softeners - Emollients  Sodium docusate (stimulant and softening) Arachis oil enema for impacted faeces Liquid Paraffin (oral solution) Side effects: anal irritation, interference with absorption of fat soluble vitamins, granulomatous reactions   Bowel cleansing solutions  Before colonic surgery, colonoscopy and radiological examinations eg Fleet, Klean-Prep, Picolax Contraindications: obstruction, GI-ulceration, perforation, CCF, toxic colitis or megacolon, ileus Side effects: nausea, bloating, cramps, vomiting    Diarrhoea Definition  Excessive fluid weight (200g/day) Increased osmotic load Excessive secretion (electrolytes and water) Exudation of protein and fluid Altered motility (rapid transit) Often combined Mechanism      Management  Rehydration, maintain fluid and electrolyte balance  NaCl absorption linked with glucose uptake (rehydr. solutions)  Antimicrobial therapy. May mask clinical picture, delay clearance of organism, increase risk of systemic invasion. Antimotility drugs Opioids  μ (motility) and δ (secretion) receptors, absorption (both)  Loperamide – Imodium        40-50x more potent than morphine Poor CNS penetration Increases transit time and sphincter tone Antisecretory against cholera toxin and some E.coli toxin T½ 11 hours, dose: 4 mg followed by 2mg doses (16mg/d max) Overdose: paralytic ileus, CNS depression Caution in IBD (toxic megacolon)  Codeine phosphate Bismuth subsalicylate Adsorbents such as Kaolin (not recommended), charcoal (insufficient data for adsorbents) Other   Diarrhoea Clostridium difficile  Clinical suspicion, test for toxins (stool)  Metronidazole PO  Vancomycin PO Irritable bowel syndrome    Recurrent abdominal pain with disturbed bowel habits 9-12% of population affected ? Pathophysiology Treatment  Dietary modification  Psychological therapies  Fibre – binding water (diarrhoea and constipation)  Antispasmodics    Anticholinergic – Hyoscyamine, methscopolamine Calcium channel antagonists and peripheral opioid receptor antagonists Mebeverine: direct effect on smooth muscle cell    Tricyclic antidepressants Analgesic and neuromodulatory properties Loperamide, codeine Antispasmodics  Antimuscarinics  Reduce motility  Quaternary amines  eg hyoscine butylbromide (Buscopan) less lipid soluble and thus less well absorbed than atropine  CI: angle-closure-glaucoma, mysthenia, paralytic ileus, pyloric stenosis and prostatic enlargement  SE: constipation, transient bradycardia, reduced bronchial secretions, urinary urgency etc Other       Direct relaxants of intestinal smooth muscle No serious side effects but avoid in paralytic ileus Alverine Mebeverine Peppermint oil (Colpermin) Pancreatitis Causes (mc) Diagnosis gallstones alcohol symptoms (abdominal pain, N&V) pancreas enzymes (amylase, lipase) USS +/- CT abdo severity scores (APACHE) Treatment rescuscitation (fluids + oxygen) symptomatic control (analgesia) prophylactic antibiotics if significant necrosis (30%) ?enteral nutritition chronic pancreatitis: pancreatin eg Creon Liver and Drugs   First pass metabolism in some drugs Hepatic biotransformation  Phase I: oxidation, reduction, hydrolysis   Cytochrome P-450 system Note: enzyme induction by eg rifampicin, carbamazepine, phenobarbitone, alcohol   Phase II: conjugation to glucoronide, sulphate, glutathion, usually resulting in inactive compounds Decrease lipid solubility and facilitate renal excretion  Export into plasma or bile -> excretion via GI tract or kidney   Enterohepatic circulation (digoxin, morphine, …) Most drugs lipophilic and thus crossing intestinal membranes Drug induced hepatotoxicity   50% of causes of acute liver failure Diagnosis      History Anorexia, nausea, fatigue Jaundice Blood tests Rule out other causes (viral, alcohol…) Overall rare Importance of postmarketing surveillance to detect liver toxicity Liver Injury and Its Patterns Navarro, V. J. et al. N Engl J Med 2006;354:731-739 Key Guidelines in the Recognition and Prevention of Hepatotoxicity in Clinical Practice Navarro, V. J. et al. N Engl J Med 2006;354:731-739 Diagnosis of Drug-Related Hepatotoxicity Navarro, V. J. et al. N Engl J Med 2006;354:731-739 Key Elements of and Caveats in Assessing Cause in the Diagnosis of Drug-Related Hepatotoxicity Navarro, V. J. et al. N Engl J Med 2006;354:731-739 Factors Predictive of a Sustained Beneficial Response to Interferon Alfa in Patients with Chronic Hepatitis Hoofnagle, J. H. et al. N Engl J Med 1997;336:347-356 References/further reading       BNF Harrison‘s Principles of Internal Medicine Pharmacology textbooks eg. Goodman&Gilman‘s Nice Guidelines Guidelines of the British Society of Gastroenterology Review articles (NEJM, Lancet…) Additional slides Flow chart for Mx of GU Gastric ulcer Entry or final state Action Action and outcome Stop NSAIDs, if used 1 Full-dose PPI for 2 months H. pylori positive, ulcer associated with NSAID use Test for H. pylori 2 H. pylori negative Full-dose PPI for 1 or 2 months H. pylori positive, ulcer not associated with NSAID use Eradication therapy 3 H. pylori positive Endoscopy and H. pylori test4 Ulcer healed, H. pylori negative Low-dose treatment as required 5 Healed Endoscopy 4 Not healed Ulcer not healed, H. pylori negative Periodic review6 Refer to specialist secondary care Return to self care Refer to specialist secondary care Flow chart for Mx of DU Duodenal ulcer Entry or final state Action Action and outcome Stop NSAIDs, if used1 Full-dose PPI for 2 months Test positive, ulcer associated with NSAID use Test for H. pylori2 Test negative Test positive, ulcer not associated with NSAID use Response Eradication therapy3 No response or relapse Re-test for H. pylori4 Positive Negative Response Full-dose PPI for 1 or 2 months No response Eradication therapy5 Response No response or relapse Low-dose treatment as required6 Response No response Exclude other causes of DU 7 Return to self care 8 Review Characteristics of Hepatitis A Virus, Hepatitis B Virus, and Hepatitis C Virus Lauer, G. M. et al. N Engl J Med 2001;345:41-52 The Replication Cycle of HBV Ganem, D. et al. N Engl J Med 2004;350:1118-1129 The Natural History of HCV Infection and Its Variability from Person to Person Lauer, G. M. et al. N Engl J Med 2001;345:41-52 Side Effects of Treatment with Interferon Alfa and Ribavirin Lauer, G. M. et al. N Engl J Med 2001;345:41-52 Pathogen-Host Interactions in the Pathogenesis of Helicobacter pylori Infection Suerbaum, S. et al. N Engl J Med 2002;347:1175-1186