GIT Pharmacology

Peptic Ulcer Disease and GIT Pharmacology

Classification of Drugs

  • Proton Pump Inhibitors (PPIs)

    • Omeprazole

    • Esomeprazole

    • Pantoprazole

    • Lansoprazole

  • H2 Receptor Antagonists

    • Ranitidine

    • Famotidine

    • Cimetidine

  • Antacids

    • Magnesium hydroxide

    • Aluminum hydroxide

    • Calcium carbonate

  • PG Analogue

    • Misoprostol

  • Mucosal Protective Agents

    • Sucralfate

  • Antibiotics

    • Bismuth subsalicylate

    • Amoxicillin

    • Clarithromycin

    • Metronidazole

Omeprazole

  • Mechanism of Action (MOA)

    • Irreversibly inhibits the H+/K+ ATPase enzyme located on the parietal cells of the stomach.

    • This inhibition blocks the final step in gastric acid secretion, leading to a significant reduction in gastric acid production.

    • Since it irreversibly inhibits the proton pump, acid secretion is reduced until new proton pumps are synthesized by parietal cells.

  • Pharmacological Actions

    1. Inhibition of gastric acid secretion.

    2. Increased gastric pH.

    3. Healing of ulcers.

    4. Eradication of H. pylori (as an adjunct therapy).

Therapeutic Uses of Omeprazole

  1. Peptic Ulcer Disease (PUD)

  2. Gastroesophageal Reflux Disease (GERD)

  3. Zollinger-Ellison Syndrome

  4. H. pylori infection

  5. NSAID-induced ulcers.

Adverse Effects of Omeprazole

  • Gastrointestinal (GIT): Nausea, vomiting, diarrhea, constipation, abdominal pain.

  • Nutritional Deficiencies:

    • Vitamin B12 deficiency

    • Hypomagnesemia

    • Osteoporotic-related fractures.

  • Clostridium difficile infection.

  • Acute interstitial nephritis.

  • Rebound acid hypersecretion.

Contraindications

  1. Hypersensitivity to omeprazole.

  2. Liver disease (hepatic impairment).

  3. Osteoporosis.

  4. Caution in pregnancy.

  5. Iron malabsorption.

Drug Interactions

  • Clopidogrel: Omeprazole can reduce the effectiveness of clopidogrel, an antiplatelet drug, by inhibiting the enzyme CYP2C19.

  • Warfarin: Omeprazole can increase the effects of warfarin, leading to an increased risk of bleeding.

  • Diazepam: Omeprazole can inhibit the metabolism of diazepam.

  • Methotrexate: High doses of methotrexate may interact with PPIs, increasing the risk of methotrexate toxicity.

  • Digoxin: Omeprazole increases the absorption of digoxin, leading to digoxin toxicity.

Ranitidine

  • Mechanism of Action (MOA)

    • Ranitidine selectively blocks H2 receptors on parietal cells of the stomach, reducing gastric acid secretion in response to histamine, gastrin, and acetylcholine (Ach).

    • This inhibition lowers both basal and stimulated gastric acid production, decreasing the acidity of the stomach.

  • Therapeutic Uses

    1. Peptic Ulcer Disease (PUD)

    2. Gastroesophageal Reflux Disease (GERD)

    3. Zollinger-Ellison Syndrome

    4. Prevention of stress ulcers.

    5. Heartburn & dyspepsia.

Adverse Effects of Ranitidine

  • CNS: Headache, dizziness, confusion.

  • GIT: Diarrhea, constipation, abdominal discomfort.

  • Cardiovascular (CVS): Bradycardia or hypotension.

  • Blood: Thrombocytopenia.

  • Endocrine: Gynecomastia & impotence.

  • Infections: Increased risk of infections, such as C. difficile.

Contraindications

  1. Hypersensitivity to ranitidine.

  2. Renal or hepatic impairment.

  3. Caution in elderly patients due to risk of CNS effects.

Anti-H. pylori Regimens

  • Triple Therapy

    • Proton Pump Inhibitor (PPI): Omeprazole or Pantoprazole.

    • Clarithromycin: 500mg twice daily.

    • Amoxicillin: 1g twice daily or Metronidazole: 500mg twice daily.

    • Duration: 10–14 days.

  • Quadruple Therapy (for resistant cases or areas with high clarithromycin resistance)

    • Proton Pump Inhibitor (PPI).

    • Bismuth subsalicylate: 300mg once daily.

    • Tetracycline: 500mg four times daily.

    • Metronidazole: 500mg three times daily.

    • Duration: 10–14 days.

Pantoprazole

  • Mechanism of Action (MOA)

    • Similar to omeprazole, pantoprazole irreversibly binds to and inhibits the H+/K+ ATPase (proton pump) in the parietal cells of the stomach, thus reducing the final step in gastric acid production.

  • Therapeutic Uses

    1. Peptic Ulcer Disease (PUD)

    2. Gastroesophageal Reflux Disease (GERD)

    3. Zollinger-Ellison Syndrome

    4. H. pylori eradication regimens.

Adverse Effects of Pantoprazole

  • Headache, nausea, diarrhea, constipation.

  • Hypomagnesemia.

  • Bone fractures.

  • Rebound acid hypersecretion.

  • Increased infections (e.g., C. difficile).

Contraindications

  1. Hypersensitivity to pantoprazole.

  2. Liver disease.

Antacids

  • Antacids are substances that neutralize stomach acid, providing rapid relief from acid-related symptoms like heartburn and indigestion.

  • Examples:

    1. Magnesium hydroxide: Neutralizes acid and has a laxative effect.

    2. Aluminum hydroxide: Neutralizes acid and may cause constipation.

    3. Calcium carbonate: Provides quick relief but may cause rebound acid production.

    4. Sodium bicarbonate: Fast acting, but not preferred due to risk of metabolic alkalosis and sodium retention.

Mechanism of Action (MOA) of Antacids

  • Antacids react with HCl in the stomach to form water and salt, thus neutralizing gastric acid and increasing the pH of the stomach.

Therapeutic Uses of Antacids

  • Symptomatic relief of heartburn, indigestion, GERD, and peptic ulcers.

Adverse Effects of Antacids

  • Diarrhea

  • Constipation

  • Hypercalcemia.

  • Metabolic alkalosis.

Colloidal Bismuth Subcitrate

  • A mucosal protective agent used in the treatment of peptic ulcer disease and part of quadruple therapy for H. pylori eradication.

Mechanism of Action (MOA)

  • Forms a protective barrier over the ulcer base by binding to proteins in the ulcer site, shielding it from acid and pepsin.

  • Stimulates the secretion of mucus and bicarbonate, providing additional protection.

  • Exhibits antibacterial action against H. pylori.

Therapeutic Uses

  1. Peptic Ulcer Disease (PUD)

  2. Chronic gastritis.

  3. Part of quadruple therapy for H. pylori eradication.

Adverse Effects

  1. Blackening of the tongue and stools.

  2. Nausea, vomiting, and constipation.

  3. Bismuth toxicity.

Contraindications

  1. Renal failure.

  2. Hypersensitivity reactions.

Metoclopramide

  • A prokinetic agent and antiemetic commonly used in the management of various disorders and to prevent nausea and vomiting.

Mechanism of Action (MOA)

  1. Dopamine D2 Receptor Antagonism: Blocks D2 dopamine receptors in the chemoreceptor trigger zone (CTZ), preventing vomiting initiation.

  2. Serotonin (5-HT4) Agonist: Stimulates the release of Ach in the GI tract, increasing motility and accelerating gastric emptying.

  3. Serotonin (5-HT3) Antagonist: At high doses, provides additional antiemetic effects.

  4. Increased Lower Esophageal Sphincter (LES) Tone: Helps prevent reflux.

Therapeutic Uses

  1. Gastroesophageal Reflux Disease (GERD)

  2. Nausea and vomiting.

  3. Gastroparesis

  4. Hiccups

  5. Prevention of aspiration.

Adverse Effects

  • Postoperative nausea and vomiting, chemotherapy-induced nausea.

  • Extrapyramidal Symptoms: Dystonia, akathisia, dyskinesia, parkinsonism.

  • Neuroleptic Malignant Syndrome.

  • Sedation.

  • Hyperprolactinemia.

Contraindications

  1. Hypersensitivity reactions.

  2. Depression, hypotension, bradycardia, diarrhea.

  3. Epilepsy.

  4. Pheochromocytoma.

Ondansetron

  • A selective serotonin (5-HT3) receptor antagonist primarily used to prevent nausea and vomiting.

Mechanism of Action (MOA)

  • Blocks serotonin 5-HT3 receptors in the central nervous system, particularly in the gastrointestinal tract.

  • Prevents the initiation of the vomiting reflex triggered by serotonin release from the enterochromaffin cells in the small intestine during nausea and vomiting.

Pharmacological Actions

  1. Anti-emetic action → prevention of nausea and vomiting induced by chemotherapy or surgery.

Therapeutic Uses

  1. Chemotherapy-induced nausea and vomiting.

  2. Radiation therapy.

  3. Postoperative nausea and vomiting.

Adverse Effects

  1. Headache.

  2. Constipation.

  3. Fatigue and dizziness.

  4. Diarrhea.

  5. QT prolongation.

  6. Serotonin syndrome.

  7. Hypersensitivity reactions.

Domperidone

  • A dopamine antagonist with antiemetic and prokinetic properties.

Mechanism of Action (MOA)

  • Blocks dopamine D2 receptors in the CTZ and in the GI tract, leading to:

    1. Antiemetic Effect: Prevents nausea and vomiting by inhibiting dopamine receptors in the CTZ.

    2. Prokinetic Effect: Enhances GI motility by increasing Ach release, improving gastric emptying and esophageal peristalsis.

Therapeutic Uses

  1. Nausea and vomiting.

  2. GERD.

  3. Gastroparesis.

  4. Dyspepsia.

  5. Lactation induction (off-label).

Adverse Effects

  1. Dry mouth and abdominal cramps.

  2. Diarrhea.

  3. Headache.

  4. Galactorrhea and amenorrhea.

  5. Gynecomastia.

  6. Cardiac arrhythmias.

  7. Sudden cardiac death (rare).

Role of Neuroleptics in Nausea and Vomiting Management

  • Neuroleptics (antipsychotics) act as effective antiemetics by blocking dopamine D2 receptors in the CTZ.

  • Mechanism of Action (MOA)

    1. Dopamine Antagonism (D2 receptors): Blocks dopamine receptors, preventing nausea and vomiting signals.

    2. Some neuroleptics also block serotonin, histamine (H1), and muscarinic cholinergic receptors, further increasing their antiemetic effects.

  • Examples:

    • Chlorpromazine

    • Prochlorperazine

    • Haloperidol

    • Droperidol

    • Olanzapine

Therapeutic Uses

  1. Chemotherapy-induced nausea and vomiting.

  2. Postoperative nausea and vomiting.

  3. Radiation therapy-induced nausea.

  4. Drug-induced vomiting.

  5. Palliative care.

Adverse Effects

  1. Extrapyramidal symptoms: Dystonia, akathisia, parkinsonism.

  2. Sedation.

  3. Anticholinergic effects.

  4. Orthostatic hypotension.

  5. QT prolongation.

  6. Metabolic effects: Dry mouth, constipation, blurred vision, urinary retention, weight gain, hyperglycemia, lipid abnormalities.

Antimotility and Antisecretory Agents

  • Classes of medications used to manage diarrhea by reducing stool frequency and improving consistency.

Antimotility Agents

  • Slow intestinal motility, allowing more time for water and electrolyte absorption, which helps decrease stool frequency and improve consistency.

    • Examples:

    • Loperamide: Slows gut movement, increases absorption of fluids and electrolytes.

    • Diphenoxylate with atropine: Reduces intestinal motility.

Antisecretory Agents

  • Reduce the secretion of fluids and electrolytes into the intestinal lumen.

    • Examples:

    • Racecadotril: An enkephalinase inhibitor that reduces intestinal fluid secretion.

    • Bismuth subsalicylate: Reduces intestinal secretions; has anti-inflammatory and antibacterial effects.

Probiotics

  • Not directly antisecretory, but restore the natural balance of gut flora, which may reduce the secretion of harmful bacterial toxins and fluids in infected bacteria.

Osmotic Laxatives
Mechanism of Action (MOA)

  • Work by increasing the amount of water in the bowel through osmosis, leading to softer stools and increased bulk, promoting bowel movement.

  • Therapeutic Uses

    1. Constipation

    2. Preparation for colonoscopy.

Common Osmotic Laxatives

  1. Polyethylene glycol (Miralax)

  2. Lactulose

  3. Magnesium hydroxide

  4. Magnesium citrate

  5. Sodium phosphate.

Adverse Effects of Osmotic Laxatives

  1. Dehydration.

  2. Electrolyte imbalance.

  3. Abdominal discomfort.

  4. Diarrhea.

  5. Renal impairment.

  6. Nausea and vomiting.

Liquid Paraffin

  • Works as a lubricant laxative by coating stools and intestinal walls to soften and facilitate passage.

Therapeutic Uses

  1. Constipation treatment.

  2. Fecal impaction.

Adverse Effects

  1. Aspiration pneumonia.

  2. Anal leakage.

  3. Malabsorption of fat-soluble vitamins (A, D, E, K).

  4. Bloating and abdominal discomfort.

  5. Lipid granulomas.

Bisacodyl

  • A stimulant laxative used to treat constipation and prepare for certain medical procedures.

Mechanism of Action (MOA)

  • Directly stimulates nerve endings in the colonic mucosa, increasing peristaltic movement and promoting water and electrolyte secretion.

Therapeutic Uses

  1. Constipation.

  2. Bowel preparation.

Adverse Effects

  1. Abdominal cramping.

  2. Diarrhea.

  3. Electrolyte imbalance.

  4. Laxative dependence.

  5. Nausea and vomiting.

Stool Softeners (Emollient Laxatives)

  • Examples: Docusate sodium, docusate calcium, docusate potassium.

Mechanism of Action (MOA)

  • Increase water and fat content in stool through surfactants, reducing surface tension and allowing a mixture of water and fats for easier passage.

Therapeutic Uses

  1. Constipation.

  2. Prevent straining.

Adverse Effects

  1. Diarrhea.

  2. Abdominal cramping.

  3. Electrolyte imbalance.

  4. Dependence.

Comparison: Cimetidine Vs. Ranitidine

Feature

Cimetidine

Ranitidine

Potency

Less potent

5 times more potent

Duration of Action

Shorter duration of action

Longer duration of action

Central Nervous System

More CNS penetration leading to CNS effects (confusion, headache, delirium)

Less CNS penetration, fewer CNS side effects

Adverse Effects

Gynecomastia, reduced sperm count, impotence, menstrual irregularities, galactorrhea in females

Fewer adverse effects compared to cimetidine

Drug Interactions

Inhibits microsomal enzymes; may lead to increased plasma levels of drugs metabolized by these enzymes causing toxicity

Fewer drug interactions

Sucralfate

Mechanism of Action (MOA)

  • Forms a protective barrier over the ulcer and damaged mucosal tissue in the stomach and duodenum by interacting with HCl to create a viscous gel that adheres to the ulcer site.

  • Protects the ulcer from further irritation by stomach acid and bile salts and promotes healing; also stimulates mucus and bicarbonate production for enhanced GI protection.

Therapeutic Uses

  1. Peptic Ulcer Disease (PUD)

  2. Gastroesophageal Reflux Disease (GERD)

  3. Prevention of stress ulcers.

Adverse Effects

  1. Constipation

  2. Dry mouth

  3. Nausea or vomiting.

Drugs Used in GERD

  1. Proton Pump Inhibitors (PPIs) → Omeprazole, Esomeprazole, Lansoprazole

  2. H2 Blockers → Ranitidine, Famotidine, Cimetidine

  3. Antacids → Aluminum hydroxide, Magnesium hydroxide, Calcium carbonate.

  4. Prokinetics → Metoclopramide, Domperidone

  5. Foaming Agents → Sucralfate, Alginates.

  6. Baclofen.

Drugs Used in Dissolution of Gallstones

  1. Ursodeoxycholic Acid (UDCA): Reduces cholesterol saturation in bile and increases bile acid solubility, used to dissolve gallstones.

  2. Chenodeoxycholic Acid (CDCA): Reduces hepatic secretion of cholesterol and enhances bile acid synthesis, can be used for the dissolution of cholesterol gallstones.

Reasons for Combining Antacids Before Administration

  1. Symptomatic relief.

  2. Mucosal protection: Rapid relief of heartburn and dyspepsia by neutralizing gastric acid, protecting gastric and duodenal mucosa by reducing acidity.

  3. Minimize adverse effects.

  4. Adjunct therapy with other medications like PPIs or H2 blockers to enhance overall effectiveness in managing acid-related disorders.

Prokinetics

  1. Metoclopramide: Used for nausea, vomiting & gastroparesis.

  2. Domperidone: Used for nausea, vomiting & helps with gastric emptying.

  3. Cisapride: Used for GERD & gastroparesis.

  4. Erythromycin: An antibiotic that also promotes gastric emptying.

  5. Prucalopride: Used for chronic constipation.

  6. Tegaserod: Used for IBS with constipation.

Digestants and Their Therapeutic Uses

  1. Pancrelipase: Treats pancreatic insufficiency (e.g., in cystic fibrosis).

  2. Pepsin: Used along with HCl in gastric achylia due to atrophic gastritis, gastric carcinoma, pernicious anemia, etc.

  3. Papain: An enzyme used in digestive supplements.

  4. Hydrochloric Acid: Used in achlorhydria.

  5. Diastase & Therasage: Used for various digestive issues.

  6. Pancreatin: A mixture of digestive enzymes.

Antiemetic Agents

  1. Ondansetron: 5-HT3 receptor antagonist used for chemotherapy-induced nausea & vomiting.

  2. Metoclopramide: Prokinetic agent that acts as an antiemetic.

  3. Promethazine: Antihistamine with antiemetic properties.

  4. Granisetron: 5-HT3 receptor antagonist for nausea & vomiting.

  5. Dexamethasone: Corticosteroid used for nausea associated with chemotherapy.

  6. Aprepitant: Neurokinin-1 antagonist for chemotherapy-induced nausea.

Classification of Laxatives

  • Bulk-forming Laxatives: Absorb water and expand in the intestine, promoting peristalsis (e.g., Psyllium, Methyl cellulose).

  • Osmotic Laxatives: Draw water into the intestine, softening stool and increasing bowel movement frequency (e.g., Lactulose, Sorbitol, Polyethylene glycol).

  • Stimulant Laxatives: Stimulate the intestinal wall to enhance peristalsis (e.g., Bisacodyl, Senna).

  • Emollient Laxatives: Soften stool by increasing water penetration (e.g., Docusate sodium, Docusate calcium).

  • Saline Laxatives: Increase osmotic pressure in the intestines, drawing water into the lumen (e.g., Magnesium hydroxide, Sodium sulfate).

Classification of Antidiarrheal Agents

  1. Opioid Derivatives: Decrease bowel motility and prolong transit time (e.g., Loperamide, Diphenoxylate).

  2. Adsorbents: Absorb excess fluid and stabilize the gut (e.g., Pectin, Kaolin).

  3. Antisecretory Agents: Reduce secretions and may have antimicrobial properties (e.g., Bismuth subsalicylate).

  4. Probiotics: Restore gut flora and improve gut function (e.g., Lactobacillus, Saccharomyces boulardii).

Role of Probiotics in Diarrhea

  • Probiotics are beneficial microorganisms that help restore the balance of gut flora disrupted during diarrhea.

  1. Enhance recovery time from acute infectious diarrhea.

  2. Prevent antibiotic-associated diarrhea: Help maintain healthy gut flora during antibiotic usage.

  3. Improve overall gut health: Potentially reduce the risk of recurrent diarrhea.

Role of Zinc in Pediatric Diarrhea

  • Zinc plays a vital role in the management of pediatric diarrhea by:

  1. Reducing the duration and severity of diarrhea.

  2. Supporting immune function: Zinc supplementation can shorten the duration of diarrhea and reduce severity.

  3. Promoting gut health: Essential for maintaining intestinal mucosal integrity and reducing the risk of future episodes.

Oral Rehydration Solution (ORS)

Composition

  • Basic ingredients:

    • Glucose

    • Sodium chloride

    • Potassium chloride

    • Sodium bicarbonate

  • A standard ORS solution contains:

    • Sodium: 75 mEq/L

    • Glucose: 75g/L

    • Potassium: 20 mEq/L

    • Bicarbonate/Citrate: 10 mEq/L

Preparation

  • Dissolve the specified amount of ORS powder in a specific volume of clean water (typically 1 liter) and ensure the solution is mixed well and used within 24 hours.

Therapeutic Uses

  1. Rehydration: Treat dehydration caused by diarrhea, vomiting, and other fluid losses.

  2. Electrolyte replenishment.

Pharmacotherapy for Inflammatory Bowel Disease (IBD)

  1. Aminosalicylates: For induction and maintenance of remission in mild to moderate IBD (e.g., Mesalamine, Sulfasalazine).

  2. Corticosteroids: Short-term management for flare-ups and moderate to severe IBD (e.g., Prednisone, Budesonide).

  3. Immunomodulators: Long-term management and maintenance of remission (e.g., Azathioprine, Mercaptopurine, Methotrexate).

  4. Antibiotics: For specific cases (e.g., Metronidazole, Ciprofloxacin).

  5. Biologics: Target specific pathways in the inflammatory process, used for moderate to severe cases (e.g., Infliximab, Adalimumab).

Non-Diarrheal Uses of ORS

  1. Hydration in Vomiting

  2. Heat Stroke / Exhaustion

  3. Post-operative Recovery