This document provides information on gastrointestinal pharmacology. It discusses topics such as peptic ulcer disease, gastroesophageal reflux disease, inflammatory bowel disease, irritable bowel syndrome, diarrhea, constipation and pancreatitis. It describes the causes, symptoms, diagnostic tests and treatment options for these conditions. Key drugs discussed include proton pump inhibitors, H2 receptor antagonists, antibiotics for Helicobacter pylori infection and various drugs for managing inflammatory bowel disease.
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:
Interaction:
renal failure, pregnancy, breast feeding
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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13. 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
mc Gastrointestinal, 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)
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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%
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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)
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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!
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17. Nonvariceal Upper GI Bleed
Resuscitate (iv access, fluids, catheter, transfusion)
Bloods (cross match, FBC, U&E, 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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18. 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
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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
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25. Inflammatory Bowel Disease
Ulcerative colitis
Diffuse mucosal inflammation limited to the colon
Crohn's disease
Features
UC
CD
patchy transmural inflammation
May affect any part of GI tract
bloody diarrhoea, colicky pain, urgency,
tenesmus
abdominal pain, diarrhoea, weight loss
intestinal obstruction
systemic symptoms
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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
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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…
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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
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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
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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
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32. Infliximab
Anti TNF-α 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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33. Principles of Managment of IBD
Assess severity
Mild and distal
Diffuse or not responding –
add oral steroids
Severe
topical steroids/aminosalicylates
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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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
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35. Severe UC
Admission for iv therapy
Close monitoring
Daily physical examination, regular vital signs, stool chart, CRP, AXR
FBC, ESR, CRP, U&E, albumin, LFT every 24-48 hours
Daily AXR if colonic dilatation (transverse >5.5cm)
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 (>8) and CRP (>45) on day 3 predict need for surgery
Consider colectomy or iv ciclosporin
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36. Medical Management of CD
Assessment
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
Site, pattern (inflammation, stricturing, fistulating), prior disease activity
Confirm disease activity (CRP, ESR)
Metronidazole +/- ciprofloxacin
Azathioprine
Infliximab
Other sites
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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 >20 mg prednisolone > 2 weeks
Relapse when dose reduction
Azathioprine (monitor FBC)
MTX, Infliximab
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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…)
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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 -> excretion via GI tract or kidney
Enterohepatic circulation (digoxin, morphine, …)
Most drugs lipophilic and thus crossing intestinal membranes
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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
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53. Liver Injury and Its Patterns
Navarro, V. J. et al. N Engl J Med 2006;354:731-739
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54. Key Guidelines in the Recognition and Prevention of Hepatotoxicity in Clinical Practice
Navarro, V. J. et al. N Engl J Med 2006;354:731-739
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55. Diagnosis of Drug-Related Hepatotoxicity
Navarro, V. J. et al. N Engl J Med 2006;354:731-739
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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 2006;354:731-739
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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 1997;336:347-356
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58. References/further reading
BNF
Harrison‘s Principles of Internal Medicine
Pharmacology textbooks eg.
Goodman&Gilman‘s
Nice Guidelines
Guidelines of the British Society of
Gastroenterology
Review articles (NEJM, Lancet…)
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60. Flow chart for Mx of GU
Gastric ulcer
Entry or final state
Action
Action and outcome
Stop NSAIDs,
if used1
Full-dose
PPI for
2 months
H. pylori positive,
ulcer associated
with NSAID use
Test for
H. pylori 2
Full-dose PPI for
1 or 2 months
H. pylori
negative
H. pylori positive,
ulcer not associated
with NSAID use
Eradication therapy3
H. pylori
positive
Endoscopy and
H. pylori test4
Ulcer healed,
H. pylori
negative
Low-dose treatment
as required5
Healed
Ulcer not healed,
H. pylori negative
Endoscopy4
Not healed
Periodic review6
Refer to specialist
secondary care
Return to self care
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Refer to specialist
secondary care
61. Flow chart for Mx of DU
Duodenal ulcer
Entry or final state
Action
Action and outcome
Stop NSAIDs,
if used1
Full-dose
PPI for
2 months
Test positive,
ulcer associated
with NSAID use
Test for H. pylori2
Test negative
Test positive,
ulcer not associated
with NSAID use
Response
Eradication
therapy3
No response
or relapse
Re-test for
H. pylori4
Response
Negative
Positive
Eradication
therapy5
Response
Return to self care
Full-dose
PPI for 1 or 2
months
No response
No response
or relapse
Low-dose
treatment as
required6
No response
Response
Review8
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Exclude other
causes of DU 7
62. Characteristics of Hepatitis A Virus, Hepatitis B Virus, and Hepatitis C Virus
Lauer, G. M. et al. N Engl J Med 2001;345:41-52
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63. The Replication Cycle of HBV
Ganem, D. et al. N Engl J Med 2004;350:1118-1129
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64. The Natural History of HCV Infection and Its Variability from Person to Person
Lauer, G. M. et al. N Engl J Med 2001;345:41-52
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65. Side Effects of Treatment with Interferon Alfa and Ribavirin
Lauer, G. M. et al. N Engl J Med 2001;345:41-52
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66. Pathogen-Host Interactions in the Pathogenesis of Helicobacter pylori Infection
Suerbaum, S. et al. N Engl J Med 2002;347:1175-1186
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67. Thank you
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Hinweis der Redaktion
Table 3. Factors Predictive of a Sustained Beneficial Response to Interferon Alfa in Patients with Chronic Hepatitis.
Table 3. Characteristics of Hepatitis A Virus, Hepatitis B Virus, and Hepatitis C Virus.
Figure 2. The Replication Cycle of HBV. HBV virions bind to surface receptors and are internalized. Viral core particles migrate to the hepatocyte nucleus, where their genomes are repaired to form a covalently closed circular DNA (cccDNA) that is the template for viral messenger RNA (mRNA) transcription. The viral mRNA that results is translated in the cytoplasm to produce the viral surface, core, polymerase, and X proteins. There, progeny viral capsids assemble, incorporating genomic viral RNA (RNA packaging). This RNA is reverse-transcribed into viral DNA. The resulting cores can either bud into the endoplasmic reticulum to be enveloped and exported from the cell or recycle their genomes into the nucleus for conversion to cccDNA. The small, peach-colored sphere inside the core particle is the viral DNA polymerase.
Figure 2. The Natural History of HCV Infection and Its Variability from Person to Person. The course of infection varies widely among persons. Factors that decrease the risk of progression include female sex and a younger age at infection; factors that increase the risk include alcohol intake, an older age at infection, male sex, and coinfection with other viruses. Persons with a favorable risk profile often do not have progressive liver disease until 30 or more years after infection. In contrast, 20 percent of persons with chronic hepatitis C will eventually have cirrhosis, and this can occur 20 years or less after infection, especially in those with alcohol abuse or coinfection with human immunodeficiency virus type 1 or hepatitis B virus. Once cirrhosis is established, the risk of hepatocellular carcinoma is 1 to 4 percent per year.
Table 2. Side Effects of Treatment with Interferon Alfa and Ribavirin.
Figure 2. Pathogen-Host Interactions in the Pathogenesis of Helicobacter pylori Infection. The host response to H. pylori participates in the induction of damage to the gastric epithelium and therefore has an integral role in H. pylori pathogenesis. During the early phase of the infection, binding of H. pylori to gastric epithelial cells, in particular through BabA and by strains harboring the cag pathogenicity island, results in the production of interleukin-8 and other chemokines, such as epithelial-cell-derived neutrophil-activating peptide 78 (ENA-78) and growth-related oncogene {alpha} (GRO-{alpha}), by epithelial cells. Nuclear factor-{kappa}B (NF-{kappa}B) and the early-response transcription-factor activator protein 1 (AP-1) are the intracellular messengers involved in this process. The chemokines secreted by epithelial cells bind to the proteoglycan scaffolding, generating a gradient along which polymorphonuclear cells (PMN) are recruited. The chronic phase of H. pylori gastritis associates an adaptive lymphocyte response with the initial innate response. Lymphocyte recruitment is facilitated by chemokine-mediated expression of vascular addressins such as vascular-cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) that are required for lymphocyte extravasation. Macrophages that participate in interleukin-8 production produce proinflammatory cytokines involved in the activation of the recruited cells, in particular T helper cells (Th0, Th1, Th2), that respond with a biased Th1 response to H. pylori. In turn, Th1-type cytokines such as interferon-{gamma} (INF-{gamma}) induce the expression of class II major histocompatibility complexes (MHC) and accessory molecules B7-1 and B7-2 by epithelial cells, making them competent for antigen presentation. The cytotoxin VacA- and Fas-mediated apoptosis induced by tumor necrosis factor {alpha} (TNF-{alpha}) leads to disruption of the epithelial barrier, facilitating translocation of bacterial antigens and leading to further activation of macrophages. Cytokines produced by macrophages can also alter the secretion of mucus, contributing to H. pylori-mediated disruption of the mucous layer. Cytokines produced in the gastric mucosa induce changes in gastric-acid secretion and homeostasis (dashed lines). TNF-{alpha}, interleukin-1{beta}, and interferon-{gamma} increase gastrin release, stimulating parietal and enterochromaffin cells and thus acid secretion. TNF-{alpha} also induces a decrease in the number of antral D cells, leading to decreased somatostatin production and indirectly enhancing acid production. LPS denotes lipopolysaccharide.