       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

Parietal cell and acid regulation

Mucosa protective factors

• Means self remedy substances • Naturally occurring • Localized in tissues • Do not normally circulate pharmacological • Diverse physiological and activities from hormones and • Differ duration of action neurotransmitters • Short involved in a response to injury • Usually action restricted to the synthesis • Sites of area

Mecanism of mucosal cells protection against acid digestion
Secretion of a barrier of adherent mucus gel from the cells Secretion of bicarbonate into the mucus layer Intrinsec resistance of the cell membranes to hydrogen ion back-diffusion High mucosal blood flow, which removes H+ from the mucosa and provides additional bicarbonate The phospholipid hydrophobic barrier

Antisecretory agents
Rising of intragastric pH above 3 for few hours - promote healing of most ulcers  Proton pump inhibitors - Omeprazole,
Famotidine, Nizatidine Lansoprazole, Pantoprazole, Esomeprazole, Rabeprazole

 H2 receptor antagonists- Cimetidine, Ranitidine,

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  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)

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: renal failure, pregnancy, breast feeding Interaction: 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  Rarely pancreatitis, bradycardia, AV block, confusion (elderly, especially cimetidine)  Rarely blood dyscrasias

Antiacids trisilicate

aluminium hydroxide, magnesium

 Neutralise gastric acidity; more prolonged effect if taken after food  Maqnesium salts neutralise acid much more rapidly than aluminium salts  Most are relatively poorly absorded from the gut  May chelate other drugs (avoid concomitant administration of other drugs)  Side effects: diarrhoea (Mg), constipation (Al)  Milk alkali syndrome (alkalosis, renal insufficiency, hypercalcemia)

Cytoprotective agents
    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)

Bismut salts
Precipitate in the environment of the stomach and then bind to glycoprotein on the base of an ulcer – complex with similar effects of sucralfate Suppress H. Pylori Risc of accumulation of bismuth - limited of 6 weeks


Cytoprotective agents
        Analogue of prostaglandine E1 Increased gastric mucus production Enhanced duodenal bicarbonate secretion Increased mucosal blood flow, which aids buffering of H+ that diffuses back across the mucosa Direct effect on gastric acid secretion, reduse endogenous histamine secretion Limit the damage caused by agents such as acid and alcohol to superficial mucosal cell Used to reduce NSAID induced gastric damage SE: diarrhoea and abdominal cramps, uterine contractions, menorragia, postmenopausal bleedings

Cytoprotective agents
 Synthetic derivative of a constituent of liquorice – it has a steroid structure  Enhances the synthesis of gastric mucus stimulating prostaglandin secretion  Increases the protective barrier in the stomach aganist acid and peptic digestion  SE: aldosterone like actions – water retention and hypokalaemia, hypertention, heart failure

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%

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

Treatment Lifestyle advice
     Dietary habits (fat, alcohol, caffeine, timing) Smoking Weight loss Raising head But little evidence for all those

    H-2 receptor antagonists PPI Antacids Prokinetics


 Dopamine receptor-blocking agent  Peripheraly it enhances gastric motility – stimulating Ach release, sensitising receptors  bioavailability 80%  SE: sedation, extrapiramidal effects, increased prolactin and aldosterone release

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

 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)

 Diet, fluid, fibre rich diet  Avoidance of constipating drugs Only then consider medication (haemorrhoids, exacerbation of angina from straining…)

     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

      Excessive fluid weight (200g/day) Increased osmotic load Excessive secretion (electrolytes and water) Exudation of protein and fluid Altered motility (rapid transit) Often combined


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
 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)

 

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

 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)


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