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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 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 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
(motility) and (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
T 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)
.

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