GI Pharmacology
Johann Graggaber SpR Clinical Pharmacology
Topics
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
Mucosa protective factors
Parietal cell and acid regulation
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
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
H. pylori
Management of dyspepsia
Therapeutic trial of acid suppressing medication H. pylori screening If alarm features
Gastric ulcer
GI bleeding Unintentional weight loss Progressive dysphagia Odynophagia Persistant vomiting Iron deficiency anaemia Mass/ suspicious barium meal
Do Endoscopy
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)
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
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)
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%
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) 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)
Sucralfate
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!
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
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
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
Precipitants
Food (fatty food, alcohol, caffeine) Smoking Obesity Medication
calcium antagonists, nitrates, theophyllines, NSAIDs, corticosteroids
Pregnancy
Usually chronic relapsing course
Diagnosis
Symptoms Empirical therapy
Endoscopy
Failure of response to therapy Alarm features Barrett’s
24-hour pH monitoring
pH < 4 Limited sensitivity
Complications
Oesophagitis Strictures, ulcers Barrett's
Barrett's
Intestinal columnar metaplasia Malignant potential Needs surveillance
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
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
CD
bloody diarrhoea, colicky pain, urgency, tenesmus abdominal pain, diarrhoea, weight loss intestinal obstruction systemic symptoms
Drugs in IBD
Aminosalicylates Corticosteroids Thiopurines Methotrexate Ciclosporin Infliximab
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
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…
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 Leucopaenia (myelotoxic) Monitor for signs of infection, sore throat Flu like symptoms after 2 to 3 weeks, liver, pancreas toxicity
Side effects
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
Ciclosporin
Inhibitor of calcineurin, preventing clonal expansion of T cell subsets Use
Active and chronic disease Steroid sparing Bridging therapy Tremor, paraesthesiae, malaise, headache, abnormal LFT Gingival hyperplasia, hirsutism Major: renal impairment, infections, neurotoxicity
Side effects
Monitor Blood pressure, FBC, renal function
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
Principles of Managment of IBD
Assess severity Mild and distal
topical steroids/aminosalicylates
Diffuse or not responding –
add oral steroids admit, iv steroids, iv fluids, ?TPN etc Avoid antimotility drugs and antispasmodics as may precipitate paralytic ileus and megacolon
Severe
Ulcerative colitis:
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
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
Medical Management of CD
Assessment
Site, pattern (inflammation, stricturing, fistulating), prior disease activity Confirm disease activity (CRP, ESR) 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
Metronidazole +/- ciprofloxacin Azathioprine Infliximab
Active intestinal disease
Fistulating and perianal
Other sites
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
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)
Increased osmotic load Excessive secretion (electrolytes and water) Exudation of protein and fluid Altered motility (rapid transit) Often combined
Mechanism
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
Bismuth subsalicylate Adsorbents such as Kaolin (not recommended), charcoal (insufficient data for adsorbents)
Other
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)
Pancreatitis
Causes (mc) Diagnosis gallstones alcohol symptoms (abdominal pain, N&V) 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
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
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
Liver Injury and Its Patterns
Navarro, V. J. et al. N Engl J Med 2006;354:731-739
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
Diagnosis of Drug-Related Hepatotoxicity
Navarro, V. J. et al. N Engl J Med 2006;354:731-739
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
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
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…)
Additional slides
Flow chart for Mx of GU
Gastric ulcer
Entry or final state
Action Action and outcome
Stop NSAIDs, if used 1
Full-dose PPI for 2 months
H. pylori positive, ulcer associated with NSAID use
Test for H. pylori 2
H. pylori negative
Full-dose PPI for 1 or 2 months
H. pylori positive, ulcer not associated with NSAID use
Eradication therapy 3
H. pylori positive
Endoscopy and H. pylori test4
Ulcer healed, H. pylori negative
Low-dose treatment as required 5
Healed
Endoscopy 4
Not healed
Ulcer not healed, H. pylori negative
Periodic review6
Refer to specialist secondary care
Return to self care
Refer to specialist secondary care
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
Positive
Negative
Response
Full-dose PPI for 1 or 2 months
No response
Eradication therapy5
Response
No response or relapse
Low-dose treatment as required6
Response
No response
Exclude other causes of DU 7
Return to self care
8 Review
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
The Replication Cycle of HBV
Ganem, D. et al. N Engl J Med 2004;350:1118-1129
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
Side Effects of Treatment with Interferon Alfa and Ribavirin
Lauer, G. M. et al. N Engl J Med 2001;345:41-52
Pathogen-Host Interactions in the Pathogenesis of Helicobacter pylori Infection
Suerbaum, S. et al. N Engl J Med 2002;347:1175-1186