GI Pharmacology

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GI Pharmacology

• Johann Graggaber
• SpR Clinical Pharmacology

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Topics

• Peptic ulcer disease/dyspepsia
• GORD
• Inflammatory bowel disease
• Irritable bowel syndrome
• Diarrhoea
• Constipation
• Pancreatitis

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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

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(No Transcript)
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Mucosa protective factors
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Parietal cell and acid regulation
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NSAIDs

• Antiinflammatory
• Analgesic
• Antipyretic
• Chemically heterogeneous
• Reversible competitive inhibitors of COX activity
  (Aspirin irreversible)
• Reduce prostaglandin synthesis (COX-1)
• ? Mucus
• ? bicarbonate
• ? blood flow
• ? proliferation of cells
• ? gastric acid secretion
• Reduce production of superoxide radicals, induce
  apoptosis, inhibit expression of adhesion
  molecules, decrease NO synthase and
  proinflammatory cytokines, modify lymphocyte
  activity and alter cellular membrane functions
• Biliary excretion and reflux of metabolites into
  stomach

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Helicobacter pylori

• Peptic ulcers
• Gastric carcinoma/lymphoma
• Mucosal atrophy
• Tests
• Urea breath test (sens. and spec. 95)
• Endoscopic (urease, histology)
• Stool antigen (sens. and spec. 95)
• (serology)
• Omit PPI for 2 weeks prior to tests

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H. pylori
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Management of dyspepsia

• Therapeutic trial of acid suppressing medication
• H. pylori screening
• If alarm features
• GI bleeding
• Unintentional weight loss
• Progressive dysphagia
• Odynophagia
• Persistant vomiting
• Iron deficiency anaemia
• Mass/ suspicious barium meal
• Do Endoscopy

Gastric ulcer
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Treatment

• Lifestyle advice
• Diet (alcohol, caffeine)
• Smoking
• Medication
• Stop NSAIDs if possible
• H-2 receptor antagonists
• Proton pump inhibitors
• H. pylori eradication
• Antacids
• Misoprostol (NSAIDs)

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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, LFT
• Rarely pancreatitis, bradycardia, AV block,
  confusion (elderly, especially cimetidine)
• Rarely blood dyscrasias

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Proton pump inhibitors

• Omeprazole, Lansoprazole, Pantoprazole,
  Esomeprazole, Rabeprazole
• Prodrugs activated in acidic secretory canaliculi
• Inhibit gastric HK 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
• mc Gastrointestinal, headache, headache dizziness
• Omeprazole impotence, gynaecomastia
• May increase risk of GI infections (reduced
  acidity)
• Note pH gt 6 necessary for platelet aggregation
• Give high dose PPI in active GI bleed (eg
  Omeprazole 8mg/hr for 72 hrs)

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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

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Other

• Antacids
• Mg and Al hydroxides
• May chelate other drugs (avoid concomitant
  administration of other drugs)
• Side effects diarrhoea (Mg), constipation (Al)
• Milk alkali syndrome (alkalosis, renal
  insufficiency, hypercalcemia)
• 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)

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Misoprostol

• PGE1 analogue
• Stimulates Gi pathway (?cAMP and ?gastric acid)
• ? blood flow and ? mucus and bicarbonate
  secretion
• Use prevention of NSAID induced injury
• Side effects diarrhoea, pain, cramps (30)
• Can cause exacerbation of IBD
• Contraindication pregnancy, caution in women of
  childbearing age
• can induce labour!

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Nonvariceal Upper GI Bleed

• Resuscitate (iv access, fluids, catheter,
  transfusion)
• Bloods (cross match, FBC, UE, clotting)
• Drugs
• Acid suppressing drugs (stabilize clot)
• Somatostatin reduces acid secretion and
  splanchnic blood flow
• Antifibrinolytic drugs tranexamic acid reduces
  need for surgery
• and mortality
• /- transfuse
• Endoscopy cause of bleeding, haemostasis
  (injection, clips, banding...), can usually wait
  until next day

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GORD

• Definition
• Abnormal reflux of gastric contents into
  oesophagus
• mucosal damage
• Prevalence
• gt 50 of population gt once a year
• 50 of patients have erosive oesophagitis
• Pathophysiology
• Antireflux barrier (sphincter)
• Acid, pepsin, trypsin, bile acids, hiatus hernia

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Symptoms

• Heartburn
• Belching
• Asthma, cough
• Hoarseness, sore throat, globus
• Alarm features
• GI bleeding
• Unintentional weight loss
• Progressive dysphagia
• Odynophagia
• Persistent vomiting
• Iron deficiency anaemia
• Mass/ suspicious barium meal

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Precipitants

• Food (fatty food, alcohol, caffeine)
• Smoking
• Obesity
• Medication
• calcium antagonists, nitrates, theophyllines,
  NSAIDs, corticosteroids
• Pregnancy
• Usually chronic relapsing course

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Diagnosis

• Symptoms
• Empirical therapy
• Endoscopy
• Failure of response to therapy
• Alarm features
• Barretts
• 24-hour pH monitoring
• pH lt 4
• Limited sensitivity

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Complications

• Oesophagitis
• Strictures, ulcers
• Barrett's

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Barrett's

• Intestinal columnar metaplasia
• Malignant potential
• Needs surveillance

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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

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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

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Drugs in IBD

• Aminosalicylates
• Corticosteroids
• Thiopurines
• Methotrexate
• Ciclosporin
• Infliximab

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Aminosalicylates

• Sulfasalazine (5-aminosalicylic acid and
  sulfapyridine as carrier substance)
• Mesalazine (5-ASA), eg Asacol, Pentasa
• Balsalazide (prodrug of 5-ASA)
• Olsalazine (5-ASA dimer cleaves in colon)
• Oral, rectal preparation
• Use
• Maintaining remission
• Active disease
• May reduce risk of colorectal cancer
• Adverse effects
• 10-45
• Nausea, headache, epigastric pain, diarrhoea,
  hypersensitivity, pancreatitis, blood disorders,
  lung disorders, myo/pericarditis
• Caution in renal impairment, pregnancy, breast
  feeding

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Corticosteroids

• Antiinflammatory agents for moderate to severe
  relapses
• eg 40mg Prednisolone
• Inhibition of inflammatory pathways (?IL
  transcription, suppression of arachidonic acid
  metabolism, lymphocyte apoptosis)
• Side effects
• Acne, moon face, oedema
• Sleep, mode disturbance
• Dyspepsia, glucose intolerance
• Cataracts, osteoporosis, myopathy

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Thiopurines

• Azathioprine, mercaptopurine
• Inhibit ribonucleotide synthesis
• Inducing T cell apoptosis by modulating cell
  signalling
• Azathioprine metabolised to mercaptopurine and
  6-thioguanine nucleotides
• Use
• Active and chronic disease
• Steroid sparing
• Side effects
• Leucopaenia (myelotoxic)
• Monitor for signs of infection, sore throat
• Flu like symptoms after 2 to 3 weeks, liver,
  pancreas toxicity

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Methotrexate

• Inhibits dihydrofolate reductase
• Probably inhibition of cytokine and eicosanoid
  synthesis
• Use
• Relapsing or active CD refractory or intolerant
  to AZA or Mercaptopurine
• Monitor FBC, LFT
• Side effects
• GI
• Hepatotoxicity, pneumonitis

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Ciclosporin

• Inhibitor of calcineurin, preventing clonal
  expansion of T cell subsets
• Use
• Active and chronic disease
• Steroid sparing
• Bridging therapy
• Side effects
• Tremor, paraesthesiae, malaise, headache,
  abnormal LFT
• Gingival hyperplasia, hirsutism
• Major renal impairment, infections,
  neurotoxicity
• Monitor
• Blood pressure, FBC, renal function

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Infliximab

• Anti TNF-a monoclonal antibody
• Potent anti inflammatory effects
• Use
• Fistulizing CD
• Severe active CD refractory/intolerant of
  steroids or immunosuppression
• iv infusion
• Side effects
• Infusion reactions
• Sepsis
• Reactivation of Tb, increased risk of Tb

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Principles of Managment of IBD

• Assess severity
• Mild and distal
• topical steroids/aminosalicylates
• Diffuse or not responding
• add oral steroids
• Severe
• admit, iv steroids, iv fluids, ?TPN etc
• Ulcerative colitis
• Avoid antimotility drugs and antispasmodics as
  may precipitate paralytic ileus and megacolon

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Medical management of UC

• Active left sided/extensive
• Aminosalicylate eg Mesalazine
• Prednisolone 40mg (for prompt response or if
  mesalazine unsuccessful) reduce dose gradually
• Azathioprine for steroid dependant disease
• Topical agents (rectal symptoms)
• Ciclosporin for severe, steroid refractory
  colitis
• Active distal UC
• Mild/Mod topical mesalazine (or steroid) oral
  mesalazine
• /- oral steroids

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Severe UC

• Admission for iv therapy
• Close monitoring
• Daily physical examination, regular vital signs,
  stool chart, CRP, AXR
• FBC, ESR, CRP, UE, albumin, LFT every 24-48
  hours
• Daily AXR if colonic dilatation (transverse
  gt5.5cm)
• Therapy
• iv fluids and electrolytes if necessary
• sc heparin (thromboembolism prophylaxis)
• ? Nutritional support
• iv steroids
• Withdrawal of antidiarrhoeal agents (can
  precipitate dilatation)
• Aminosalicylates
• Topical therapy
• /- surgical referral (colonic dilatation)
• Stool frequency (gt8) and CRP (gt45) on day 3
  predict need for surgery
• Consider colectomy or iv ciclosporin

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Medical Management of CD

• Assessment
• Site, pattern (inflammation, stricturing,
  fistulating), prior disease activity
• Confirm disease activity (CRP, ESR)
• Active intestinal disease
• Mild aminosalicylate
• Mod/severe oral corticosteroids (reduce
  gradually over 8 weeks)
• Severe iv steroids
• Elemental/polymeric diets
• TPN (fistulating)
• Azathioprine as steroid sparing agent
• Consider surgery
• Fistulating and perianal
• Metronidazole /- ciprofloxacin
• Azathioprine
• Infliximab
• Other sites

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Maintenance of remission of CD

• STOP SMOKING
• Mesalazine of limited benefit
• Azathioprine effective but toxicity
• Methotrexate
• Infliximab
• Steroid refractory disease
• Definition
• Active disease on gt20 mg prednisolone gt 2 weeks
• Relapse when dose reduction
• Azathioprine (monitor FBC)
• MTX, Infliximab

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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)

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Laxatives

• Bulk-forming
• Stimulant
• Faecal softeners
• Osmotic laxatives
• Bowel cleansing solutions
• Oral
• Rectal-suppositories, enemas
• General Contraindications intestinal perforation
  and obstruction

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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

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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

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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

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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

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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

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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.

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Antimotility drugs

• Opioids
• µ (motility) and d (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)

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Diarrhoea

• Clostridium difficile
• Clinical suspicion, test for toxins (stool)
• Metronidazole PO
• Vancomycin PO

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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

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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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Pancreatitis

• Causes (mc) gallstones
• alcohol
• Diagnosis symptoms (abdominal pain, NV)
• pancreas enzymes (amylase, lipase)
• USS /- CT abdo
• severity scores (APACHE)
• Treatment rescuscitation (fluids oxygen)
• symptomatic control (analgesia)
• prophylactic antibiotics if significant
  necrosis (30)
• ?enteral nutritition
• chronic pancreatitis pancreatin eg Creon

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Liver and Drugs

• First pass metabolism in some drugs
• Hepatic biotransformation
• Phase I oxidation, reduction, hydrolysis
• Cytochrome P-450 system
• Note enzyme induction by eg rifampicin,
  carbamazepine, phenobarbitone, alcohol
• Phase II conjugation to glucoronide, sulphate,
  glutathion, usually resulting in inactive
  compounds
• Decrease lipid solubility and facilitate renal
  excretion
• Export into plasma or bile -gt excretion via GI
  tract or kidney
• Enterohepatic circulation (digoxin, morphine, )
• Most drugs lipophilic and thus crossing
  intestinal membranes

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Drug induced hepatotoxicity

• 50 of causes of acute liver failure
• Diagnosis
• History
• Anorexia, nausea, fatigue
• Jaundice
• Blood tests
• Rule out other causes (viral, alcohol)
• Overall rare
• Importance of postmarketing surveillance to
  detect liver toxicity

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Liver Injury and Its Patterns
Navarro, V. J. et al. N Engl J Med
2006354731-739
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Key Guidelines in the Recognition and Prevention
of Hepatotoxicity in Clinical Practice
Navarro, V. J. et al. N Engl J Med
2006354731-739
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Diagnosis of Drug-Related Hepatotoxicity
Navarro, V. J. et al. N Engl J Med
2006354731-739
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Key Elements of and Caveats in Assessing Cause in
the Diagnosis of Drug-Related Hepatotoxicity
Navarro, V. J. et al. N Engl J Med
2006354731-739
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Factors Predictive of a Sustained Beneficial
Response to Interferon Alfa in Patients with
Chronic Hepatitis
Hoofnagle, J. H. et al. N Engl J Med
1997336347-356
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References/further reading

• BNF
• Harrisons Principles of Internal Medicine
• Pharmacology textbooks eg. GoodmanGilmans
• Nice Guidelines
• Guidelines of the British Society of
  Gastroenterology
• Review articles (NEJM, Lancet)

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Additional slides
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Flow chart for Mx of GU
Gastric ulcer
Stop
NSAIDs
,
if used
1
Full-dose
Test for
Full-dose PPI for
H. pylori
H. pylori
positive,
PPI for
H. pylori
2
1 or 2 months
negative
ulcer associated
2 months
with NSAID use
H. pylori
positive,
ulcer not associated
with NSAID use
Eradication therapy
3
H. pylori
Healed
Low-dose treatment
Ulcer healed,
Endoscopy and
positive
Endoscopy
4
as required
5
H. pylori
test
4
H. pylori
negative
Ulcer not healed,
Not healed
H. pylori
negative
Periodic review
6
Refer to specialist
Refer to specialist
Return to self care
secondary care
secondary care
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Flow chart for Mx of DU
Duodenal ulcer
Stop
NSAIDs
,
if used
1
Full-dose
Test negative
Test positive,
Test for
H. pylori
2
PPI for
ulcer associated
2 months
with NSAID use
Test positive,
ulcer not associated
with NSAID use
Eradication
Response
therapy
3
No response
or relapse
Full-dose
Re-test for

PPI for 1 or 2
H. pylori
4
Negative
Response
months
Positive
No response
Low-dose
Eradication
Exclude other
treatment as
therapy
5
causes
of DU
7
No response
No response
required
6
or relapse
Response
Response
Review
8
Return to self care
62
Characteristics of Hepatitis A Virus, Hepatitis B
Virus, and Hepatitis C Virus
Lauer, G. M. et al. N Engl J Med 200134541-52
63
The Replication Cycle of HBV
Ganem, D. et al. N Engl J Med 20043501118-1129
64
The Natural History of HCV Infection and Its
Variability from Person to Person
Lauer, G. M. et al. N Engl J Med 200134541-52
65
Side Effects of Treatment with Interferon Alfa
and Ribavirin
Lauer, G. M. et al. N Engl J Med 200134541-52
66
Pathogen-Host Interactions in the Pathogenesis of
Helicobacter pylori Infection
Suerbaum, S. et al. N Engl J Med
20023471175-1186