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 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
• Differ from hormones and neurotransmitters
• Short duration of action
• Usually involved in a response to injury
• Sites
area
of action restricted to the synthesis
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 therapy
For 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
GORD
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
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 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 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)
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 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

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)