GI DrugsGI Drugs

PHC 5409BPHC 5409B

Dr. T.C. PetersonDr. T.C. Peterson

Drugs for GI Tract disordersDrugs for GI Tract disorders

DRUGS THAT REDUCE GASTRIC ACIDITYDRUGS THAT REDUCE GASTRIC ACIDITY CYTOPROTECTIVE DRUGS CYTOPROTECTIVE DRUGS DRUGS FOR DRUGS FOR HELICOBACTER PYLORI HELICOBACTER PYLORI INFECTIONINFECTION DRUGS FOR INFLAMMATORY BOWEL DISEASES DRUGS FOR INFLAMMATORY BOWEL DISEASES PROKINETIC DRUGS PROKINETIC DRUGS LAXATIVES LAXATIVES ANTIDIARRHEAL AGENTS ANTIDIARRHEAL AGENTS ANTIEMETICSANTIEMETICS

Peptic Ulcer diseasePeptic Ulcer disease

Characterized by inflamed lesions and Characterized by inflamed lesions and ulcersulcers

Causes: Causes: Excessive acid productionExcessive acid production Bile acid refluxBile acid reflux Advancing ageAdvancing age IschemiaIschemia Inhibition of PG synthesisInhibition of PG synthesis Infection with Helicobacter pyloriInfection with Helicobacter pylori

Drugs that reduce gastric acidityDrugs that reduce gastric acidity

H2 receptor antagonistsH2 receptor antagonists Proton pump inhibitorsProton pump inhibitors Muscarinic antagonistsMuscarinic antagonists ProstaglandinsProstaglandins AntacidsAntacids SucralfateSucralfate

Cytoprotective DrugsCytoprotective Drugs

SucralfateSucralfate

MisoprostolMisoprostol

Drugs for H.pylori infectionDrugs for H.pylori infection

Multi-drug therapy is usually usedMulti-drug therapy is usually used Common combination:Common combination:

Gastric acid secretion inhibitor Gastric acid secretion inhibitor

(PPI or H2 blocker) (PPI or H2 blocker)

and two of the following:and two of the following:

Amoxicillin, Bismuth, Clarithromycin, Amoxicillin, Bismuth, Clarithromycin, Metronidazole, TetracyclineMetronidazole, Tetracycline

Inflammatory Bowel DiseaseInflammatory Bowel Disease

Chronic Inflammatory disease:Chronic Inflammatory disease: Crohn's Disease (CD)  - full thickness  - full thickness

inflammation anywhere in gastrointestinal tract inflammation anywhere in gastrointestinal tract Ulcerative Colitis (UC) - inflammation of superficial - inflammation of superficial

layers, continuous from rectum layers, continuous from rectum Lymphocytic Colitis - collections of lymphocytes Lymphocytic Colitis - collections of lymphocytes

without granulomas without granulomas Collagenous Colitis - collagenous deposition in Collagenous Colitis - collagenous deposition in

subepithelial zone, rectum and colon subepithelial zone, rectum and colon Diagnosis is clinical but requires tissue biopsy for Diagnosis is clinical but requires tissue biopsy for

confirmation and classification confirmation and classification

IBD  -  Treatment  IBD  -  Treatment  

Acute Moderate to Severe ExacerbationAcute Moderate to Severe Exacerbation - Usually in - Usually in patients with known disease, now active patients with known disease, now active – Glucocorticoids Glucocorticoids – Broad spectrum antibioticsBroad spectrum antibiotics (including metronidazole) (including metronidazole) – Intravenous cyclosporineIntravenous cyclosporine may be used after 7-10 may be used after 7-10

days if responses are poor days if responses are poor

Chronic Therapy (Remission Maintenance)   Chronic Therapy (Remission Maintenance)           – 5-aminosalicylate (5-ASA)5-aminosalicylate (5-ASA)– Azathioprine, 6-mercaptopurine (6-MP) and Azathioprine, 6-mercaptopurine (6-MP) and

methotrexatemethotrexate

IBD drugsIBD drugs

SulfasalazineSulfasalazine– First line therapy in most patients with acute or chronic IBD First line therapy in most patients with acute or chronic IBD – Congener of sulfapyridine and 5-aminosalicylic acid linked by an Congener of sulfapyridine and 5-aminosalicylic acid linked by an

azo bond azo bond – Attenuates inflammation in the large bowel only Attenuates inflammation in the large bowel only – Compound is cleaved to composite groups by colonic bacteria Compound is cleaved to composite groups by colonic bacteria

(azoreductase) (azoreductase) – Requires 5-28 days for efficacy Requires 5-28 days for efficacy – Contradindicated in patients with sulfa allergy; 15% of patients Contradindicated in patients with sulfa allergy; 15% of patients

will discontinue drug will discontinue drug – Side effects: cytopenias, pancreatitis, hepatitis, rash, diarrhea, Side effects: cytopenias, pancreatitis, hepatitis, rash, diarrhea,

male infertility male infertility

IBD drugsIBD drugs

OlsalazineOlsalazine– Dimer of 5-ASA linked by azo bond which is split by Dimer of 5-ASA linked by azo bond which is split by

colonic bacteria colonic bacteria – Contraindicated in patients with salicylate allergy; no Contraindicated in patients with salicylate allergy; no

sulfa moiety sulfa moiety – Main side effect is diarrhea (~25% of patients) Main side effect is diarrhea (~25% of patients) – Main use is in patients who cannot tolerate Main use is in patients who cannot tolerate

sulfasalazine sulfasalazine

Appears to be as effective as sulfasalazine for Appears to be as effective as sulfasalazine for mild to moderate IBD mild to moderate IBD

IBD drugsIBD drugs

MesalamineMesalamine

– Delayed release 5-ASA (ie. coated with acrylic-based Delayed release 5-ASA (ie. coated with acrylic-based resin) dissolves at pH 6 resin) dissolves at pH 6

– Mainly released in distal ileum and colon; Mainly released in distal ileum and colon;

IBD drugsIBD drugs

AzathioprineAzathioprine– Side Effects: Pancreatitis (~5%), Bone marrow Side Effects: Pancreatitis (~5%), Bone marrow

suppression (~2%), hepatitis suppression (~2%), hepatitis – Mildly effective as single agent, does prevent Mildly effective as single agent, does prevent

flares of disease and maintain remissions flares of disease and maintain remissions – Usually permits reduction in glucocorticoid Usually permits reduction in glucocorticoid

dose required for suppression of disease dose required for suppression of disease – Note: this drug is metabolized to 6-MP Note: this drug is metabolized to 6-MP

IBD drugsIBD drugs

6-Mercaptopurine (6-MP)6-Mercaptopurine (6-MP) – Effective in prevention of relapses and possibly in Effective in prevention of relapses and possibly in

active disease active disease – Most patients require >17 weeks to see initial effect Most patients require >17 weeks to see initial effect – 6-MP and AZA are effective in 50-70% of patients with 6-MP and AZA are effective in 50-70% of patients with

IBD IBD – Side effects include bone marrow suppression and Side effects include bone marrow suppression and

pancreatitis, hepatitis pancreatitis, hepatitis

IBD drugsIBD drugs

MethotrexateMethotrexate – 20-25mg/week given i.m. in refractory Crohn's disease 20-25mg/week given i.m. in refractory Crohn's disease

disease disease – Extremely well tolerated Extremely well tolerated – Allowing lowering of steroid doses and control of Allowing lowering of steroid doses and control of

disease disease – Recommended now in nearly all patients requiring Recommended now in nearly all patients requiring

higher dose prednisone higher dose prednisone

IBD drugIBD drug

CyclosporineCyclosporine – Good response initially to iv form, usually within 48 Good response initially to iv form, usually within 48

hours hours – Relapses common when drug is stopped Relapses common when drug is stopped – This agent shows most rapid onset of activity in This agent shows most rapid onset of activity in

steroid refractory disease steroid refractory disease – Reduces need for surgical resection in fulminant UC Reduces need for surgical resection in fulminant UC – Dose must be monitored closely Dose must be monitored closely

Novel Therapies for IBD Novel Therapies for IBD

Specific Cytokine Blockers Specific Cytokine Blockers – IL-1 receptor antagonist (IL-1RA) IL-1 receptor antagonist (IL-1RA) – TNFTNF blockers blockers

Other immunosuppressive agents may be effective Other immunosuppressive agents may be effective – Cyclosporine Cyclosporine – Rapamycin Rapamycin – FK506 and other immunosuppressives FK506 and other immunosuppressives

Fish Oil (EPA) Fish Oil (EPA) – May reduce production of inflammatory leukotrienes and May reduce production of inflammatory leukotrienes and

thromboxanes thromboxanes – Suppresses IL-1 and TNF production Suppresses IL-1 and TNF production – Reduced CD exacerbations at 1 year Reduced CD exacerbations at 1 year

IBD drugsIBD drugs

Tumor Necrosis Factor Alpha (TNFTumor Necrosis Factor Alpha (TNF) ) BlockadeBlockade

– Activity predicted on the basis of certain Activity predicted on the basis of certain animal models animal models

– Has good activity in Crohn's Disease, Has good activity in Crohn's Disease, including fistula healing including fistula healing

Prokinetic DrugsProkinetic Drugs

Drugs used to increase GI motilityDrugs used to increase GI motility Increase activity of smooth muscle in the Increase activity of smooth muscle in the

esophagus, stomach and intestineesophagus, stomach and intestine examples:examples:

– Cisapride: stimulates 5-HT receptorsCisapride: stimulates 5-HT receptors– Metoclopramide: blocks dopamine D2 receptorsMetoclopramide: blocks dopamine D2 receptors

Antidiarrheal AgentsAntidiarrheal Agents

Bismuth subsalicylate, diphenoxylate, Bismuth subsalicylate, diphenoxylate, kaolin-pectin, loperamide, and polycarbophil kaolin-pectin, loperamide, and polycarbophil

Opioid DrugsOpioid Drugs

Antiemetic drugsAntiemetic drugs

Dopamine D2 receptor antagonistsDopamine D2 receptor antagonists

Serotonin 5HT3 receptor antagonistsSerotonin 5HT3 receptor antagonists

Other antiemetics Other antiemetics

• • Dimenhydrinate and scopolamine Dimenhydrinate and scopolamine

Review of drugs for GI DisordersReview of drugs for GI Disorders

DRUGS THAT REDUCE GASTRIC ACIDITY DRUGS THAT REDUCE GASTRIC ACIDITY

Histamine 2 receptor antagonists Histamine 2 receptor antagonists

• • Cimetidine, famotidine, and ranitidineCimetidine, famotidine, and ranitidine

Proton pump inhibitors Proton pump inhibitors

Lansoprazole and omeprazole Lansoprazole and omeprazole

Muscarinic receptor antagonists Muscarinic receptor antagonists

• • Atropine and pirenzepineAtropine and pirenzepine

Gastric antacids Gastric antacids

Aluminum and magnesium hydroxides and calcium Aluminum and magnesium hydroxides and calcium carbonate carbonate

Review of drugs for GI DisordersReview of drugs for GI Disorders

Cytoprotective drugsCytoprotective drugs

Misoprostol and sucralfateMisoprostol and sucralfate

Drugs for Drugs for Helicobacter pylori infection Helicobacter pylori infection

• • Amoxicillin, bismuth, clarithromycin, metronidazole, and Amoxicillin, bismuth, clarithromycin, metronidazole, and tetracyclinetetracycline

DRUGS FOR INFLAMMATORY BOWEL DISEASES DRUGS FOR INFLAMMATORY BOWEL DISEASES

• • .Azathioprine, infliximab, mercaptopurine, mesalamine, .Azathioprine, infliximab, mercaptopurine, mesalamine, metronidazole, prednisolone, and sulfasalazine metronidazole, prednisolone, and sulfasalazine

Review of drugs for GI DisordersReview of drugs for GI Disorders

PROKINETIC DRUGSPROKINETIC DRUGS

• • Cisapride and metoclopramide Cisapride and metoclopramide ANTIDIARRHEAL AGENTS ANTIDIARRHEAL AGENTS

• • Bismuth subsalicylate, diphenoxylate, kaolin-pectin, Bismuth subsalicylate, diphenoxylate, kaolin-pectin, loperamide, and opiates loperamide, and opiates

ANTIEMETICSANTIEMETICS

Serotonin 5-HT3 receptor antagonists Serotonin 5-HT3 receptor antagonists

• • Granisetron and ondansetron Granisetron and ondansetron

Dopamine D2Dopamine D2 receptor antagonistsreceptor antagonists • • Metoclopramide Metoclopramide