GASTRO-INTESTINAL Pharmacology
Peptic ulcer disease/dyspepsia GORD Inflammatory bowel disease Irritable bowel syndrome Diarrhoea Constipation Pancreatitis
Dyspepsia / Peptic ulcer disease Dyspepsi psia:
upp upper ab abdo pa pain/discomfo mfort (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 Introduction
Means self remedy Naturally occurring substances Localized in tissues Do not normally circulate Diverse physiological and pharmacological activities from hormones and Differ neurotransmitters Short duration of action Usually involved in a response to injury Sites of action restricted to the synthesis area
Mecanism of mucosal cells protection against acid digestion -
Secretion of a barrier of adherent 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, 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 promote heal healing ing of most ulcers ulcers
Proton pump inhibitors - Omeprazole, Lansoprazole, Pantoprazole, Esomeprazole, Rabeprazole
H2 receptor antagonistsFamot idi ne, N zat ne idi ne, i i idi idi ne
met idi ne, Ci met idi ne,
Rani t tidi ne, i di ne,
-
Proton pump inhibitors Omeprazole, Lansoprazole, Pantoprazole, Esomeprazole, Rabeprazole
Prodrugs
activated in acidic secretory canaliculi Inhibit gastric H+K+ ATPase i rrevers rreversi bly bly 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 Omeprazole ± impotence, impotence, gynaecomasti gynaecomastia a May increase risk of GI infections inf ections (reduced acidity) Note: pH > 6 necessary for platelet aggregation Give high dose PPI in active GI bleed (eg Omeprazole 8mg/hr for 72 hrs)
met idi ne, H2 rece recept ptor or anta antago gonis nists ts - Ci met idi ne, Rani t tidi ne, Famot idi ne, N zat ne i di ne, idi ne, i i idi idi ne
Competitive and selective inhibition of histamine H-2 receptor Suppress 24 hr gastric secretion secre tion by 70% Less effective than PPI Caution: Caution: renal failure, failure, pregnancy, pregnancy, breast breast feeding Interac Interacti tion: on: Cimeti Cimetidin dine e binds binds to CYP 450 (retards oxidative drug metaboli metabolism) sm) note interactio interactions ns with warfarin, warfarin, phenytoin, phenytoin, theophylline. Side effects Well tolerated, less than 3% adverse effects Diarrhoea, headache, drowsy, fatigue, constipation, CNS Rarely pancreatitis, bradycardia, AV block, confusion confu sion (elderly, especially cimetidine) Rarely blood dyscrasias
Antiacids -
alumi ni um um hy d r ox id e, magnesi um um drox id e,
tr i is lic ate i l i c ate
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 Side effects effects:: diarrho diarrhoea ea (Mg), constipation (Al) l k alkal i i synd rome rome (alkalosis, renal insufficiency, M i ilk hypercalcemia)
Cytoprotective Cytoprotective agents Sucralfate Forms sticky polymer in acidic environment Inhibits hydrolysis of mucous proteins by pepsin 1 g bd to 1g qds SE: constipation, constipation, aluminium aluminium absorption absorption (avoid (avoid in severe renal impairment due to risk of encephalopathy) Bismut Bismut salts alts -
-
Precipitate in the environment of the stomach and then bind to glycoprotein on the base base of an ulce ulcerr ± comple complex x with similar effects of sucralfate Suppress H. Pylori Risc of a accumulati ccumulation on of bismuth bismuth - limited limited of of 6 weeks weeks
Cytoprotective agents Misoprostol
Analogue of prostaglandine E1 Increased gastric mucus production Enhanced duodenal bicarbonate secretion Increased mucosal blood flow, flow, which aids buffering of H+ that diffuses back across the mucosa mu cosa 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 Carbenoxolone
Synthetic derivative of a constituent of liqu liquor oric ice e ± it has has a steroid structure Enhances the synthesis of gastric of gastric mucus stimulating prostaglandin secretion Increases the protective barrier in the stomach aganist acid and peptic digestion SE: aldost aldosterone erone like like actions actions ± water water retention 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%
GOR D 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
GOR D 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
Prokinetics
Metoclopramide
Dopamine receptor-blocking agent Peripheraly it enhances gastric motility ± stimulating Ach release, sensitising sensitising receptors bioavailability bioavailability 80% SE: sedation, extrapiramidal effects, increased prolactin and aldosterone release
Inflammatory Inflammatory Bowel Disease Ulcerative colitis
Diffuse mucosal inflammation inflammation limited to the colon
Crohn's disease
Features UC
CD
patchy transmural inflammation May affect any part of GI tract
bloody diarrhoea, colicky pain, urgency, tenesmus abdominal pain, diarrhoea, weight loss intestinal obstruction systemic symptoms
Drugs in IBD
Aminosalicylates Corticosteroids Thiopurines Methotrexate Ciclosporin 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 consider medication medication (haemorrhoi (haemorrhoids, ds, exacerbati exacerbation on of angina from straining«)
Laxatives
Bulk-forming Stimulant Faecal softeners Osmotic laxatives Bowel cleansing solutions
Oral Rectal-suppositories, Rectal-suppositories, enemas
General Contraindications: intestinal perforation and obstruction
Bulk-forming laxatives
Increase faecal mass which stimulates peristalsis
Bulk/softness/hydration dependant 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)
spaghula I spaghula
(Fybogel, I sogel) sogel) ethyl c e e ) M ethyl cellulose llulose ( C Cevela velac Ster c u ol) cul l i ia (Normac ol) Contraindica Contraindication tion:: intestinal intestinal obstruction, 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 (Dul isacodyl (Dul c c o-lax), o-lax), usually 5-10mg noc te te Anthraquinone
Laxatives Require activation in colon (bacteria), onset of action delayed (6-12 hours) Senokot), plant derivative Senna ( Senokot), Danthron ( C C oo-d anthramer) anthramer) possibly c ar ar ci ci nogen nogenic , only use in terminally ill
Docusate
Sodium stimulant and softening
Glycerol suppositories (Parasympathomi met met ic ic s suc h as bethanec hol, hol, neost i i mi n rarely used ) Side effects: effects: cramps, diarrhoea, diarrhoea, hypokalaemia hypokalaemia
Osmotic laxatives Osmotical Osmotically ly mediated mediated water retenti retention on
Nondigest Nondigestible ible sugars sugars and alcoho alcohols ls
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, M ic ic ralax ic ro-enema) ralax M ic ro-enema)
Polyethylene Glycol-Electrolyte Solutions - Macrogels
Sequester fluid in bowel, poorly absorbed M ovicol ovicol
aeca call so softe ftene ners rs - Emol Emolli lien ents ts Fae
Sodium docusate (stimulant and softening)
Arach rachis is
Liquid
enema for impacted faeces oil oil enema
Paraffin (oral solution) Side effects: effects: anal irritation, irritation, interferenc interference e with with absorption of fat soluble vitamins, granulomatous granuloma tous reactions
Bowel cleansing solutions
Before colonic colonic surgery, colonoscopy and radiological examinations
olax eg Fleet, Klean-Prep, P ic ic olax
Contrai Contraindi ndicati cations: ons: obstructi obstruction, on, GI-ulcera GI-ulceratio tion, n, perforation, CCF, toxic colitis or megacolon, ileus
Side Side effects: effects: nausea, nausea, bloa bloatin ting, g, cramps, cramps, vomiting
Diarrhoea Definition
Excessive fluid weight (200g/day)
Mechanism
Increased osmotic load Excessive secretion (electrolytes and water) Exudation of protein and fluid Altered motility (rapid transit) Often combined
Management ehydration, maintain fluid and electrolyte balance R ehydration, 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
Loperamide ± I mo modi um um
(motility) and (secretion) (secretion) receptors, receptors, absorptio absorption n (both) (motility)
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, hours, dose: 4 mg followed followed by 2mg doses doses (16mg/d max) Overdose: paralytic ileus, CNS depression Caution in IBD (toxic megacolon)
C odeine odeine
phosphate
Other
Bismuth subsalicylate Adsorbents such as Kaolin (not recommended), charcoal (insufficient data for adsorbents)
Diarrhoea Clostridium
difficile Clinical suspicion, test for toxins (stool) Metronidazole PO Vancomycin PO
Irritable bowel syndrome
R ecurrent ecurrent
abdominal pain with disturbed bowel habits 9-12% of population affected ? Pathophysiology
Treatment Dietary modificati m odification on Psychological therapies binding water (diarrhoea (diarrhoea and constip constipati ation) on) Fibre ± binding Antispasmodics
Anticholinergic ± H yos yosc yam yami ne, ne, methsc opolam opolami ne ne Calcium channel antagonists and peripheral opioid receptor antagonists ebever i ine: n M ebever e: 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-clo angle-closure-gl sure-glaucoma aucoma,, mysthenia, mysthenia, paralytic paralytic ileus, pyloric stenosis and prostatic enlargement SE: constipat constipation, ion, transient transient bradycardia, bradycardia, reduced bronchial bronchial secretions, urinary urgency etc Other
.
Direct relaxants of intestinal smooth muscle No serious side effects but avoid in paralytic ileus n Alver i ine e ebever i ine n M ebever e Peppermi nt nt oi l (Colpermin) l (Colpermin)
