GASTRO-INTESTINAL Pharmacology

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 ulcersdefects in mucosa extending through muscularis mucosae

PrevalencePUD 5-10% lifetimedyspepsia 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

• Differ from hormones and 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 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, Lansoprazole, Pantoprazole, Esomeprazole, Rabeprazole

H2 receptor antagonists- Cimetidine, Ranitidine, Famotidine, Nizatidine

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 - aluminium hydroxide, magnesium trisilicate

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

Sucralfate 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

Misoprostol 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

Carbenoxolone 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 therapyFor 7 (14) days twice daily eg

full dose PPI + Amoxicillin + Clarithromycin/Metronidazole

Effective in 80-85%

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

GORDTreatmentLifestyle 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 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 bloody diarrhoea, colicky pain, urgency,

tenesmus CD abdominal pain, diarrhoea, weight loss

intestinal obstructionsystemic 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 drugsOnly 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 laxativesOsmotically 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

DiarrhoeaDefinition

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 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 drugsOpioids

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

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 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)

.