Gastrointestinal Pharmacology

Roy Krishna, Ph.D. FCP.

Gastrointestinal Pharmacology

• Emesis• Diarrhea• Inflammatory Bowel Disease• Irritable Bowel Syndrome• Gastroesophageal Reflux Disease (GERD)• Peptic Ulcer Disease (PUD)

Antiemetics

• Emesis is caused by stimulation of chemoreceptor trigger zone (CTZ) and the vomiting center.

• Affected by chemical stimuli and afferent input from vestibular system.

• Activation of dopamine and serotonin receptors

Antiemetics

Prevention and treatment of vomiting

Treatment of chemotherapy-induced vomiting– Phenothiazines. (Prochlorperazine)

– 5HT3 inhibitors (Ondansetron)

– Metoclopramide– Butyrophenones (Droperidol)

– H1-antihistamines (Meclizine, Loratidine)

– Dronabinol

Laxatives

Bulk-forming • Act on the stool that causes reflex

contraction of the bowel (Psyllium)

Stool softening • Acts on hard or impacted stool (Docusate)

Stimulants• Increase peristalsis (Senna)

Antidiarrheal Agents

• Diarrhea is a result of:

Increased GI tract motility

Reduced fluid absorprtion

Infection.

Antidiarrheal objectives are to reduce peristalsis, act as adsorbents and modify fluid and electrolyte transport

Antidiarrheal Agents

• Opioids and their derivatives are the most effective antidiarrheal agents

• Should be selected for maximal antidiarrheal properties and minimal CNS effects

Diphenoxylate (Lomotil®)

Loperamide (Imodium®)

Gastroesophageal Reflux Disease

Retrograde movement of gastric contents from stomach into esophagus:

• Heartburn• Gastroesophageal regurgitation• Esophageal inflammation• Erosive Esophagitis

Gastroesophageal Reflux Disease

• Lifestyle Changes• Antacids

• H2 – antagonists

• Proton pump inhibitors (PPI’s)

Inflammatory Bowel Disease

– Ulcerative Colitis and Crohn’s disease– Ongoing inflammation of the GI

mucosa– Inflammation by an antigen driven

response?

Inflammatory Bowel DiseaseTherapeutic Approach

• Suppression of inflammation and alleviation of signs and symptoms:

Corticosteroids

Immunosuppressive antimetabolites,

Monoclonal antibodies

Aminosalicylates

Pharmacological Management of Peptic Ulcer

Disease

Peptic Ulcer

• Lesions in stomach or duodenum occurring as a result of excessive pepsin and acid activity.

• Zollinger-Ellison Syndrome: Hypersecretion due to gastrin secreting tumor

Peptic Ulcer Disease

Balance between aggressive forces (gastric acid and pepsin) and defensive factors (lining) of the mucosa ensures maintenance of integrity of the GI mucosa.

Peptic UlcerPathogenesis

1) Causative factors- NSAID use, alcohol, smoking, stress

2) Acid hypersecretion ( Zollinger Ellison Syndrome)

3) Helicobacter pylori (H.pylori) infection

Peptic UlcerClinical Manifestations

– Epigastric pain (“burning sensation”)– Dyspepsia– Perforation and bleeding.– Abdominal/nocturnal pain– Nausea, vomitting– Anorexia

Increased AttackIncreased Attack HyperacidityHyperacidity

Weak defenseWeak defense Helicobacter pyloriHelicobacter pylori Stress, drugs, smoking Stress, drugs, smoking

NormalNormal

Peptic UlcerHelicobacter Pylori

Peptic UlcerTherapeutic Objectives

1) Elimination of H. pylori

2) Reduction of gastric acid secretion or acid neutralization

3) Protection of gastric mucosa from further damage

Peptic UlcerTherapeutic Approach

– Antacids

– H2 –antagonists (Ranitidine, Famotidine)

– Cytoprotective Agents (Bismuth Subsalicylate)

– Proton Pump Inhibitors (Omeprazole, Esomaprazole)

– Antimicrobial Agents (Amoxicillin, Clarithromycin)

– Triple Therapy (proton pump inhibitor + 2 antimicrobial agents)

Peptic UlcerTherapeutic Approach

Proton Pump Inhibitors (PPI): Omeprazole (Prilosec) Lansoprazole (Prevacid) Esomeprazole (Nexium) Pantoprazole (Protonix) Rabeprazole (AcipHex)

Peptic Ulcer DiseaseEradication of H.pylori

First-line therapy for patients colonized with H.pylori.– Rapid healing of peptic ulcers– Low recurrence rates– Combination therapy (“triple therapy”)-proton

pump inhibitor (PPI) with metronidazole or amoxicillin plus clarithromycin – 7-14 days

90% eradication rate.

Peptic Ulcer DiseaseH.pylori Eradication Regimens

• PPI –based 3 –drug regimens:

First-line therapy

*Omeprazole 20mg b.i.d

+

Clarithromycin 500mg b.i.d

+

Amoxicillin 1g b.i.d/Metronidazole 500mg b.i.d

Zollinger-Ellison (ZE) Syndrome

• Gastric acid hypersecretion and concurrent peptic ulceration.

• PPI’s are the drugs of choice• Omeprazole-60 mg/d effectively controls acid

output and relieves symptoms• Gradual reduction in dose over time is

recommended.