gi drugs outline

PharmacologyPharmacologyPharmacologyPharmacology

Drugs that Affect the

Gastrointestinal System

Drugs that Affect the

Gastrointestinal System

TopicsTopicsTopicsTopics

• Peptic Ulcer Disease

• Constipation

• Diarrhea

• Emesis

• Digestion

• Peptic Ulcer Disease

• Constipation

• Diarrhea

• Emesis

• Digestion

Peptic Ulcer DiseasePeptic Ulcer DiseasePeptic Ulcer DiseasePeptic Ulcer Disease

Factors thatIncrease Acidity

Factors thatIncrease Acidity

Factors thatProtect Against

Acidity

Factors thatProtect Against

Acidity

Peptic Ulcer DiseasePeptic Ulcer DiseasePeptic Ulcer DiseasePeptic Ulcer Disease

• Factors Increasing– H. pylori

– NSAIDs

– Acidic agents

– Pepsin

– Smoking

• Factors Increasing– H. pylori

– NSAIDs

– Acidic agents

– Pepsin

– Smoking

• Factors Decreasing– Mucus production

– Buffers

– Blood flow

– Prostaglandins

• Factors Decreasing– Mucus production

– Buffers

– Blood flow

– Prostaglandins

Regulation of Gastric Acid Regulation of Gastric Acid SecretionSecretionRegulation of Gastric Acid Regulation of Gastric Acid SecretionSecretion

HH22 Receptor Antagonists Receptor AntagonistsHH22 Receptor Antagonists Receptor Antagonists

• Inhibits gastric acid secretion

• No effect on H1 receptors

• cimetidine (Tagamet®)

• ranitidine (Zantac®)

• famotidine (Pepcid®)

• nizatidine (Axid®)

• Inhibits gastric acid secretion

• No effect on H1 receptors

• cimetidine (Tagamet®)

• ranitidine (Zantac®)

• famotidine (Pepcid®)

• nizatidine (Axid®)

HH22 Receptor Antagonists Receptor AntagonistsHH22 Receptor Antagonists Receptor Antagonists

• Indications:– PUD– GERD– Prevention of aspiration pneumonia

• Indications:– PUD– GERD– Prevention of aspiration pneumonia

Proton Pump InhibitorsProton Pump InhibitorsProton Pump InhibitorsProton Pump Inhibitors

• K+H+ATPase (Proton Pump)

• Irreversible inhibition– Must synthesize new enzyme– Long duration

• omeprazole (Prilosec®)

• lansoprazole (Prevacid®)

• K+H+ATPase (Proton Pump)

• Irreversible inhibition– Must synthesize new enzyme– Long duration

• omeprazole (Prilosec®)

• lansoprazole (Prevacid®)

AnticholinergicsAnticholinergicsAnticholinergicsAnticholinergics

• pirenzepine (Gastrozepine®)

• Other anticholinergics have too many side effects and are not used

• pirenzepine (Gastrozepine®)

• Other anticholinergics have too many side effects and are not used

Prostaglandin AnalogProstaglandin AnalogProstaglandin AnalogProstaglandin Analog

• misoprostol (Cytotec®)– Approved for treating PUD due to long term

NSAID use

• misoprostol (Cytotec®)– Approved for treating PUD due to long term

NSAID use

AntacidsAntacidsAntacidsAntacids

• Increase pH of gastric environment

• Hydroxides– Aluminum – Magnesium

• Carbonates– Calcium

• Increase pH of gastric environment

• Hydroxides– Aluminum – Magnesium

• Carbonates– Calcium

AntacidsAntacidsAntacidsAntacids

• Most OTC drugs are combinations– DiGel®

– Amphojel®

– Maalox®

– Milk of Magnesia®

– Mylanta®

• Most OTC drugs are combinations– DiGel®

– Amphojel®

– Maalox®

– Milk of Magnesia®

– Mylanta®

AntibioticsAntibioticsAntibioticsAntibiotics

• Aimed at eliminating H. pylori

• bismuth (Pepto-Bismol®)

• metronidazole (Flagyl®)

• amoxicillin (Amoxil®)

• tetracycline (Achromycin V®)

• Aimed at eliminating H. pylori

• bismuth (Pepto-Bismol®)

• metronidazole (Flagyl®)

• amoxicillin (Amoxil®)

• tetracycline (Achromycin V®)

Stool FormationStool FormationStool FormationStool Formation

Water absorbed in colon (~90%)– Excessive absorption

• Constipation: hard, dehydrated stool

• Increases strain on defecation

• Harmful for subset of patients– Recent episiotomy, colostomy, hemorrhoids,

cardiovascular disease

– Inadequate absorption• Diarrhea: soft, non-formed, liquid stool

Water absorbed in colon (~90%)– Excessive absorption

• Constipation: hard, dehydrated stool

• Increases strain on defecation

• Harmful for subset of patients– Recent episiotomy, colostomy, hemorrhoids,

cardiovascular disease

– Inadequate absorption• Diarrhea: soft, non-formed, liquid stool

TermsTermsTermsTerms

LaxativeLaxative Production of soft, formed stool over 1 or more days

Production of soft, formed stool over 1 or more days

CatharticCathartic Rapid, intense fluid evacuation of bowel.

Rapid, intense fluid evacuation of bowel.

LaxativesLaxativesLaxativesLaxatives

• Bulk forming

• Surfactants

• Stimulants

• Osmotics

• Bulk forming

• Surfactants

• Stimulants

• Osmotics

Bulk Forming LaxativesBulk Forming LaxativesBulk Forming LaxativesBulk Forming Laxatives

• Absorb water• Soften and enlarge

stool• Fecal swelling

promotes peristalsis

• Absorb water• Soften and enlarge

stool• Fecal swelling

promotes peristalsis

• methylcellulose (Citrucel®)

• psyllium (Metamucil®)• Polycarbophil

• methylcellulose (Citrucel®)

• psyllium (Metamucil®)• Polycarbophil

Surfanctant LaxativesSurfanctant LaxativesSurfanctant LaxativesSurfanctant Laxatives

• Lowers surface tension– Facilitates water

penetration

• Lowers surface tension– Facilitates water

penetration

• Docusate salts– Colace®

– Modane Soft®)

• Docusate salts– Colace®

– Modane Soft®)

Stimulant LaxativesStimulant LaxativesStimulant LaxativesStimulant Laxatives

• Stimulate peristalsis• Increases water and

electrolytes secretion into intestinal lumen

• Decreases water and electrolyte reabsorption

• Stimulate peristalsis• Increases water and

electrolytes secretion into intestinal lumen

• Decreases water and electrolyte reabsorption

• Phenylolpthalein – (Ex-Lax®, Feen-a-

Mint®, Correctol®)

• bisacodyl (Ducolax®)

• Phenylolpthalein – (Ex-Lax®, Feen-a-

Mint®, Correctol®)

• bisacodyl (Ducolax®)

Osmotic LaxativesOsmotic LaxativesOsmotic LaxativesOsmotic Laxatives

• Poorly absorbed salts remain in fecal matter

• Pull water into lumen

• Poorly absorbed salts remain in fecal matter

• Pull water into lumen

• Magnesium hydroxid (Milk of Magnesia®)

• Magnesium hydroxid (Milk of Magnesia®)

AntidiarrhealAntidiarrhealAntidiarrhealAntidiarrheal

• Diarrhea is usually a compensatory action…– Treatment aimed at cause, no symptom

• Opioid receptors in GI tract decrease motility– Increase time for water reabsorbtion

• Diarrhea is usually a compensatory action…– Treatment aimed at cause, no symptom

• Opioid receptors in GI tract decrease motility– Increase time for water reabsorbtion

Antidiarrheal AgentsAntidiarrheal AgentsAntidiarrheal AgentsAntidiarrheal Agents

• paregoric/opium tincture

• diphenoxylate (Lomotil®)

• defenoxin (Motofen®)

• loperamide (Imodium®)

• paregoric/opium tincture

• diphenoxylate (Lomotil®)

• defenoxin (Motofen®)

• loperamide (Imodium®)

Vomiting StimulusVomiting StimulusVomiting StimulusVomiting Stimulus

AntiemeticsAntiemeticsAntiemeticsAntiemetics

• Serotonin (5HT) Antagonists

• Dopamine (DA) Antagonists

• Anticholinergics (muscarinic blockers)

• Cannabinoids

• Serotonin (5HT) Antagonists

• Dopamine (DA) Antagonists

• Anticholinergics (muscarinic blockers)

• Cannabinoids

Serotonin AntagonistsSerotonin AntagonistsSerotonin AntagonistsSerotonin Antagonists

• Used to treat side effects of chemotherapy-induced emesis

• condansetron (Zofran®)

• Doesn’t affect dopamine receptors no extrapyramidal effects

• Granisetron (Kytril®)

• Used to treat side effects of chemotherapy-induced emesis

• condansetron (Zofran®)

• Doesn’t affect dopamine receptors no extrapyramidal effects

• Granisetron (Kytril®)

Dopamine AntagonistsDopamine AntagonistsDopamine AntagonistsDopamine Antagonists

• Phenothiazines– prochloraperazine (Compazine®)– promethazine (Phenergan®)

• Butyrophenones– haloperidol (Haldol®)– droperidol (Inapsine®)

• metoclopramide (Reglan®)

• Phenothiazines– prochloraperazine (Compazine®)– promethazine (Phenergan®)

• Butyrophenones– haloperidol (Haldol®)– droperidol (Inapsine®)

• metoclopramide (Reglan®)

CannabinoidsCannabinoidsCannabinoidsCannabinoids

• Tetrahydrocannabinol (THC)– Active ingredient in marijuana– Dronabinol (Marinol®)– Nabilone (Cesamet®)

• Tetrahydrocannabinol (THC)– Active ingredient in marijuana– Dronabinol (Marinol®)– Nabilone (Cesamet®)

Digestion AidsDigestion AidsDigestion AidsDigestion Aids

• Useful for inactive vagal stimulus/bypassed duodenum

• Pancreatin (Entozyme®)

• Pancrelipase (Viokase®)

• Useful for inactive vagal stimulus/bypassed duodenum

• Pancreatin (Entozyme®)

• Pancrelipase (Viokase®)

TopicsTopicsTopicsTopics

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

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

www.freelivedoctor.com

Dyspepsia / Peptic ulcer diseaseDyspepsia / Peptic ulcer diseaseDyspepsia / Peptic ulcer diseaseDyspepsia / Peptic ulcer disease

Dyspepsia: upper abdo pain/discomfort (fullness, bloating, distension, nausea)

Peptic ulcersdefects in mucosa extending through muscularis mucosae

PrevalencePUD 5-10% lifetimedyspepsia 25-40%

Aetiology (most common) H.pylori NSAIDs

Dyspepsia: upper abdo pain/discomfort (fullness, bloating, distension, nausea)

Peptic ulcersdefects in mucosa extending through muscularis mucosae

PrevalencePUD 5-10% lifetimedyspepsia 25-40%

Aetiology (most common) H.pylori NSAIDs


Mucosa protective factorsMucosa protective factorsMucosa protective factorsMucosa protective factors


Parietal cell and acid regulationParietal cell and acid regulationParietal cell and acid regulationParietal cell and acid regulation


NSAIDsNSAIDsNSAIDsNSAIDs

• 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

• 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 pyloriHelicobacter pyloriHelicobacter pyloriHelicobacter 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

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. pyloriH. pyloriH. pyloriH. pylori


Management of dyspepsiaManagement of dyspepsiaManagement of dyspepsiaManagement 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

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


TreatmentTreatmentTreatmentTreatment

Lifestyle advice– Diet (alcohol, caffeine…)– Smoking

Medication– Stop NSAIDs if possible– H-2 receptor antagonists– Proton pump inhibitors– H. pylori eradication– Antacids– Misoprostol (NSAIDs)

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 antagonistsH2 receptor antagonistsH2 receptor antagonistsH2 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

• 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


Proton pump inhibitorsProton pump inhibitorsProton pump inhibitorsProton 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)

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 eradicationH. pylori eradicationH. pylori eradicationH. 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%

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%


OtherOtherOtherOther

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)

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)


MisoprostolMisoprostolMisoprostolMisoprostol

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!

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 BleedNonvariceal Upper GI BleedNonvariceal Upper GI BleedNonvariceal 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

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


GORDGORD GORDGORD

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

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


SymptomsSymptomsSymptomsSymptoms

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

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


PrecipitantsPrecipitantsPrecipitantsPrecipitants

Food (fatty food, alcohol, caffeine) Smoking Obesity Medication

calcium antagonists, nitrates, theophyllines, NSAIDs, corticosteroids

Pregnancy

Usually chronic relapsing course

Food (fatty food, alcohol, caffeine) Smoking Obesity Medication

calcium antagonists, nitrates, theophyllines, NSAIDs, corticosteroids

Pregnancy

Usually chronic relapsing course


DiagnosisDiagnosisDiagnosisDiagnosis

Symptoms Empirical therapy

Endoscopy Failure of response to therapy Alarm features Barrett’s

24-hour pH monitoring pH < 4 Limited sensitivity

Symptoms Empirical therapy

Endoscopy Failure of response to therapy Alarm features Barrett’s

24-hour pH monitoring pH < 4 Limited sensitivity


ComplicationsComplicationsComplicationsComplications

Oesophagitis Strictures, ulcers Barrett's

Oesophagitis Strictures, ulcers Barrett's


BarrettBarrett''ssBarrettBarrett''ss

Intestinal columnar metaplasia

Malignant potential Needs surveillance

Intestinal columnar metaplasia

Malignant potential Needs surveillance


TreatmentTreatmentTreatmentTreatment

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

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 DiseaseInflammatory Bowel DiseaseInflammatory Bowel DiseaseInflammatory 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 obstructionsystemic symptoms

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 obstructionsystemic symptoms


Drugs in IBDDrugs in IBDDrugs in IBDDrugs in IBD

Aminosalicylates Corticosteroids Thiopurines Methotrexate Ciclosporin Infliximab

Aminosalicylates Corticosteroids Thiopurines Methotrexate Ciclosporin Infliximab


AminosalicylatesAminosalicylatesAminosalicylatesAminosalicylates

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

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


CorticosteroidsCorticosteroidsCorticosteroidsCorticosteroids

• 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…

• 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…


ThiopurinesThiopurinesThiopurinesThiopurines

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

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


MethotrexateMethotrexateMethotrexateMethotrexate

• 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

• 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


CiclosporinCiclosporinCiclosporinCiclosporin

• 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

• 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


InfliximabInfliximabInfliximabInfliximab

• 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

• 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 IBDPrinciples of Managment of IBDPrinciples of Managment of IBDPrinciples 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

• 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


Medical management of UCMedical management of UCMedical management of UCMedical 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

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 UCSevere UCSevere UCSevere 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 surgeryConsider colectomy or iv ciclosporin

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 surgeryConsider colectomy or iv ciclosporin


Medical Management of CDMedical Management of CDMedical Management of CDMedical 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

• 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


Maintenance of remission of CDMaintenance of remission of CDMaintenance of remission of CDMaintenance 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

• 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


ConstipationConstipationConstipationConstipation

• 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…)

• 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…)


LaxativesLaxativesLaxativesLaxatives

• Bulk-forming• Stimulant• Faecal softeners• Osmotic laxatives• Bowel cleansing solutions

• Oral• Rectal-suppositories, enemas

General Contraindications: intestinal perforation and obstruction

• Bulk-forming• Stimulant• Faecal softeners• Osmotic laxatives• Bowel cleansing solutions

• Oral• Rectal-suppositories, enemas

General Contraindications: intestinal perforation and obstruction


Bulk-forming laxativesBulk-forming laxativesBulk-forming laxativesBulk-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

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 LaxativesStimulant LaxativesStimulant LaxativesStimulant 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

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 laxativesOsmotic laxativesOsmotic laxativesOsmotic 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

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 - EmollientsFaecal softeners - EmollientsFaecal softeners - EmollientsFaecal 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

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 solutionsBowel cleansing solutionsBowel cleansing solutionsBowel 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

• 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


DiarrhoeaDiarrhoeaDiarrhoeaDiarrhoea

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.

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 drugsAntimotility drugsAntimotility drugsAntimotility 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

Other Bismuth subsalicylate Adsorbents such as Kaolin (not recommended), charcoal (insufficient data for adsorbents)

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

Other Bismuth subsalicylate Adsorbents such as Kaolin (not recommended), charcoal (insufficient data for adsorbents)


DiarrhoeaDiarrhoeaDiarrhoeaDiarrhoea

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

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


Irritable bowel syndromeIrritable bowel syndromeIrritable bowel syndromeIrritable 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

• 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


AntispasmodicsAntispasmodicsAntispasmodicsAntispasmodics

• 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)

• 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)


PancreatitisPancreatitisPancreatitisPancreatitis

Causes (mc) gallstonesalcohol

Diagnosis 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 nutrititionchronic pancreatitis: pancreatin eg Creon

Causes (mc) gallstonesalcohol

Diagnosis 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 nutrititionchronic pancreatitis: pancreatin eg Creon


Liver and DrugsLiver and DrugsLiver and DrugsLiver 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

• 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 hepatotoxicityDrug induced hepatotoxicityDrug induced hepatotoxicityDrug 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

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


Navarro, V. J. et al. N Engl J Med 2006;354:731-739

Liver Injury and Its Patterns



Key Guidelines in the Recognition and Prevention of Hepatotoxicity in Clinical Practice



Diagnosis of Drug-Related Hepatotoxicity



Key Elements of and Caveats in Assessing Cause in the Diagnosis of Drug-Related Hepatotoxicity


Hoofnagle, J. H. et al. N Engl J Med 1997;336:347-356

Factors Predictive of a Sustained Beneficial Response to Interferon Alfa in Patients with Chronic Hepatitis


References/further readingReferences/further readingReferences/further readingReferences/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…)

• 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…)


Test forH. pylori 2

H. pylori

negative

Gastric ulcer

Full-dose PPI for1 or 2 months

Periodic review6

Return to self care

Stop NSAIDs,if used1

Endoscopy4Healed

Not healed

Refer to specialist secondary care

Low-dose treatmentas required5

Full-dosePPI for

2 months

H. pyloripositive,

ulcer associatedwith NSAID use

H. pyloripositive,ulcer not associatedwith NSAID use

Eradication therapy3

Ulcer not healed, H. pylorinegative

Ulcer healed,

H. pylorinegative

H. pyloripositive Endoscopy and

H. pyloritest4

Refer to specialist secondary care

Entry or final state

ActionAction and outcome

Flow chart for Mx of GUFlow chart for Mx of GU


Test for H. pylori2Test negative

Eradication therapy3

Test positive,ulcer not associatedwith NSAID use

Duodenal ulcer

Full-dosePPI for 1 or 2

months

Re-test for H. pylori4

No responseor relapse

Negative

Positive

Low-dosetreatment as

required6

Review8

Response

No responseEradication

therapy5

Response

No responseor relapse

No response

Exclude other causesof DU7

Response

Response

Return to self care

Stop NSAIDs, if used1

Full-dosePPI for

2 months

Test positive,

ulcer associatedwith NSAID use

Entry or final state

ActionAction and outcome

Flow chart for Mx of DUFlow chart for Mx of DU


Lauer, G. M. et al. N Engl J Med 2001;345:41-52

Characteristics of Hepatitis A Virus, Hepatitis B Virus, and Hepatitis C Virus


Ganem, D. et al. N Engl J Med 2004;350:1118-1129

The Replication Cycle of HBV


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


Pathogen-Host Interactions in the Pathogenesis of Helicobacter pylori Infection


gi drugs outline

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