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GI Pharmacology

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Title: GI Pharmacology


1
GI Pharmacology
  • Johann Graggaber
  • SpR Clinical Pharmacology

2
Topics
  • Peptic ulcer disease/dyspepsia
  • GORD
  • Inflammatory bowel disease
  • Irritable bowel syndrome
  • Diarrhoea
  • Constipation
  • Pancreatitis

3
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

4
(No Transcript)
5
Mucosa protective factors
6
Parietal cell and acid regulation
7
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

8
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

9
H. pylori
10
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
11
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)

12
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

13
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)

14
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

15
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)

16
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!

17
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

18
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

19
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

20
Precipitants
  • Food (fatty food, alcohol, caffeine)
  • Smoking
  • Obesity
  • Medication
  • calcium antagonists, nitrates, theophyllines,
    NSAIDs, corticosteroids
  • Pregnancy
  • Usually chronic relapsing course

21
Diagnosis
  • Symptoms
  • Empirical therapy
  • Endoscopy
  • Failure of response to therapy
  • Alarm features
  • Barretts
  • 24-hour pH monitoring
  • pH lt 4
  • Limited sensitivity

22
Complications
  • Oesophagitis
  • Strictures, ulcers
  • Barrett's

23
Barrett's
  • Intestinal columnar metaplasia
  • Malignant potential
  • Needs surveillance

24
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

25
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

26
Drugs in IBD
  • Aminosalicylates
  • Corticosteroids
  • Thiopurines
  • Methotrexate
  • Ciclosporin
  • Infliximab

27
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

28
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

29
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

30
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

31
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

32
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

33
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

34
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

35
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

36
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

37
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

38
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)

39
Laxatives
  • Bulk-forming
  • Stimulant
  • Faecal softeners
  • Osmotic laxatives
  • Bowel cleansing solutions
  • Oral
  • Rectal-suppositories, enemas
  • General Contraindications intestinal perforation
    and obstruction

40
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

41
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

42
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

43
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

44
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

45
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.

46
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)

47
Diarrhoea
  • Clostridium difficile
  • Clinical suspicion, test for toxins (stool)
  • Metronidazole PO
  • Vancomycin PO

48
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

49
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)

50
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

51
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

52
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

53
Liver Injury and Its Patterns
Navarro, V. J. et al. N Engl J Med
2006354731-739
54
Key Guidelines in the Recognition and Prevention
of Hepatotoxicity in Clinical Practice
Navarro, V. J. et al. N Engl J Med
2006354731-739
55
Diagnosis of Drug-Related Hepatotoxicity
Navarro, V. J. et al. N Engl J Med
2006354731-739
56
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
57
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
58
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)

59
Additional slides
60
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
61
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
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