GI Pharmacology and Therapeutics PDF

GI Pharmacology and Therapeutics Pathophysiology of GERD Definition: GERD is caused by the retrograde movement of stomach contents into the esophagus due to lower esophageal sphincter (LES) dysfunction. Symptoms: Heartburn, regurgitation, chest pain, chronic cough, laryngitis....

GI Pharmacology and Therapeutics Pathophysiology of GERD Definition: GERD is caused by the retrograde movement of stomach contents into the esophagus due to lower esophageal sphincter (LES) dysfunction. Symptoms: Heartburn, regurgitation, chest pain, chronic cough, laryngitis. Risk Factors: o Obesity, smoking, alcohol use. o Dietary triggers: spicy foods, caffeine, citrus, chocolate. o Pregnancy. o Medications: NSAIDs, calcium channel blockers, bisphosphonates. Guidelines for Management: o Lifestyle Modifications: Weight loss, elevating head of bed, avoiding late meals, reducing triggers. o Step-Up Therapy: Start with H2 blockers for mild cases; progress to PPIs for moderate to severe symptoms. o Maintenance Therapy: Long-term PPI use only for severe erosive esophagitis or Barrett’s esophagus. The choice of medication depends on the severity and frequency of GERD symptoms. a. Antacids Mechanism: Neutralize stomach acid. Examples: Tums (calcium carbonate), Maalox, Mylanta. Best Use: o For mild and occasional heartburn. o Provides immediate, short-term relief. Limitations: o Not suitable for chronic or severe GERD. o May interfere with absorption of some medications. b. H2 Receptor Antagonists (H2 Blockers) Mechanism: Block histamine on parietal cells, reducing acid production. Examples: Famotidine (Pepcid), Ranitidine (withdrawn in many markets), Cimetidine (Tagamet). Best Use: o For mild to moderate GERD symptoms. o Effective for nocturnal acid suppression. Limitations: o Tolerance can develop with long-term use. o Less effective than PPIs for healing esophagitis. c. Proton Pump Inhibitors (PPIs) Mechanism: Irreversibly inhibit the H+/K+ ATPase (proton pump) in parietal cells, reducing acid production. Examples: Omeprazole (Prilosec), Esomeprazole (Nexium), Pantoprazole (Protonix), Lansoprazole (Prevacid). Best Use: o First-line for moderate to severe GERD and erosive esophagitis. o Long-term control in chronic GERD. Limitations: o Takes 1-4 days for full effect (not for immediate relief). o Long-term use risks: Vitamin B12 deficiency, hypomagnesemia, osteoporosis, and increased risk of infections (e.g., C. difficile). d. Prokinetic Agents (Optional for Select Patients) Mechanism: Improve motility and LES tone, promoting gastric emptying.  Examples: Metoclopramide (Reglan), Domperidone (not available in all countries). Best Use: o Adjunct in GERD with delayed gastric emptying. Limitations: o Metoclopramide has significant side effects (e.g., tardive dyskinesia). e. Alginates Mechanism: Form a viscous barrier that floats on stomach contents, reducing reflux. Examples: Gaviscon. Best Use: o Adjunct for symptomatic relief in mild GERD. Pathophysiology of Peptic Ulcer Disease (PUD) Definition: Peptic ulcers are mucosal erosions in the stomach or duodenum due to acid- pepsin activity. Causes: o H. pylori infection (most common worldwide). o NSAID use: Inhibits prostaglandin synthesis, reducing mucosal defense. o Stress, Zollinger-Ellison Syndrome (rare). Complications: o Bleeding (melena, hematemesis). o Perforation (acute abdomen). o Gastric outlet obstruction (vomiting, early satiety). Management Guidelines: o H. pylori testing for all diagnosed with PUD. o Use PPI prophylaxis in patients on long-term NSAIDs, especially if high-risk (elderly, anticoagulants). o Discontinue NSAIDs if possible; switch to COX-2 inhibitors if required. 2. General Treatment Principles a. Reduce Gastric Acid Lowering stomach acid allows ulcers to heal and prevents further injury. Same therapies as GERD. + 1. Cytoprotective Agents: a. Sucralfate: Forms a protective barrier over ulcers. b. Misoprostol: A prostaglandin analog that protects the gastric mucosa (used for NSAID-induced ulcers). b. Eradicate H. pylori For H. pylori-positive ulcers, eradication is critical to prevent recurrence. 1. Triple Therapy: a. PPI + Amoxicillin + Clarithromycin. b. Duration: 10-14 days. c. Replace Amoxicillin with Metronidazole in penicillin-allergic patients. 2. Quadruple Therapy:  a. PPI + Bismuth subsalicylate + Metronidazole + Tetracycline. b. Duration: 10-14 days. c. Often used in areas with high clarithromycin resistance or after triple therapy failure. 3. Concomitant Therapy: a. PPI + Amoxicillin + Clarithromycin + Metronidazole. b. Duration: 10-14 days. c. Discontinue NSAIDs Stop NSAID use if possible. If NSAIDs are necessary: o Use PPI prophylaxis. o Consider COX-2 selective inhibitors (e.g., celecoxib) for lower GI risk. The gastric acid pump, also known as the proton pump, is an enzyme system in the stomach lining that plays a crucial role in producing gastric acid (hydrochloric acid, HCl). Here's how it works: Key Components Location: The proton pump, scientifically called H+/K+ ATPase, is located on the parietal cells of the stomach lining.  Function: It actively secretes hydrogen ions (H⁺) into the stomach, combining with chloride ions (Cl⁻) to form HCl. Steps of the Gastric Acid Pump Mechanism 1. Activation by Stimulants: a. The pump is activated by stimuli that signal the need for digestion, such as: i. Gastrin: A hormone that stimulates acid production. ii. Histamine: Released from enterochromaffin-like (ECL) cells. iii. Acetylcholine: Released from parasympathetic nerves. (Rest and Digest) 2. Ionic Exchange Process: a. H+ Secretion: i. Inside the parietal cell, water (H₂O) is split into hydrogen ions (H⁺) and hydroxide ions (OH⁻). ii. The proton pump exchanges potassium ions (K⁺) from the stomach lumen for these hydrogen ions, using energy from ATP. b. Cl⁻ Secretion: i. Chloride ions (Cl⁻) are transported from the blood into the stomach lumen via separate channels. 3. Formation of Hydrochloric Acid (HCl): a. H⁺ and Cl⁻ combine in the stomach lumen to form HCl. 4. Regulation of Stomach Acidity: a. The high concentration of HCl in the stomach lowers the pH (to about 1-2), aiding digestion by: i. Denaturing proteins. ii. Activating enzymes like pepsin. iii. Killing harmful microorganisms. Inhibition of the Pump Proton pump inhibitors (PPIs) like omeprazole and esomeprazole work by irreversibly binding to and inhibiting the H+/K+ ATPase enzyme, effectively reducing acid production and treating acid-related conditions such as GERD and ulcers. 1. Acid Reducers & Proton Pump Inhibitors (PPIs) Mechanism of Action: Inhibit H+/K+ ATPase enzyme in gastric parietal cells, reducing stomach acid production.  Common Medications: Omeprazole Brand Names: Prilosec, Prilosec OTC Esomeprazole Brand Names: Nexium, Nexium 24HR Pantoprazole Brand Names: Protonix Lansoprazole Brand Names: Prevacid, Prevacid 24HR Indications: GERD, Peptic Ulcer Disease, Zollinger-Ellison Syndrome, NSAID-induced ulcers. Adverse Effects: o Increased risk of fractures (especially in postmenopausal women). o Hypomagnesemia (monitor levels in chronic use). o C. difficile infection (watch for diarrhea in long-term users). o Potential kidney injury and B12 deficiency with prolonged use. Prescribing Pearls: o Use the lowest effective dose for the shortest duration to manage symptoms. o Taper slowly when discontinuing after prolonged use to avoid rebound hyperacidity. o Avoid long-term use in patients without a clear indication (e.g., functional dyspepsia). Pharmacokinetics: o Administer 30-60 minutes before the first meal of the day for optimal effect. 2. Histamine H2 Blockers Mechanism of Action: Block histamine H2 receptors on gastric parietal cells, decreasing acid secretion. Common Medications: Famotidine (Zantac), Cimetidine (less commonly used), Nizatidine.  Indications: GERD, Peptic Ulcer Disease, mild heartburn, nocturnal acid suppression. Adverse Effects: o Cimetidine: Gynecomastia, drug interactions via CYP450 inhibition. o Headaches and rare dizziness. o CNS effects (confusion, agitation) in elderly patients with renal impairment. Prescribing Pearls: o Preferred for on-demand relief of symptoms or mild cases of GERD. o Use cautiously in elderly patients; adjust dose in renal impairment. o Combine with PPIs for breakthrough nighttime symptoms in GERD. PPIs vs. H2 Blockers: Feature PPIs H2 Blockers Mechanism Inhibits H+/K+ ATPase Blocks H2 receptors Onset 1-3 hours 30-60 minutes Duration Up to 24 hours 6-12 hours Potency Higher Lower Adverse Effects Fractures, C. diff risk CNS effects in elderly Comparison of Histamine H2 Blockers vs. Proton Pump Inhibitors (PPIs) Histamine H2 Blockers (e.g., ranitidine, famotidine) Mechanism: Inhibit histamine receptors on parietal cells, decreasing acid secretion. Uses: Effective for: o Mild GERD or occasional heartburn. o Duodenal ulcers (short-term use). o Nocturnal acid suppression.  Advantages: Faster onset (30-60 minutes), generally less potent than PPIs. Dosing Example: Famotidine 20 mg BID or 40 mg QHS for GERD. Proton Pump Inhibitors (e.g., omeprazole, pantoprazole) Mechanism: Irreversibly inhibit H+/K+ ATPase, suppressing gastric acid production. Uses: First-line for: o Severe GERD. o Erosive esophagitis. o Peptic ulcer disease (PUD), including H. pylori-associated ulcers. o Zollinger-Ellison syndrome. Advantages: Longer-lasting acid suppression (up to 24 hours). Dosing Example: Omeprazole 20 mg QD, 30 minutes before breakfast. Key Prescribing Points H2 Blockers: Short-term or as-needed use for mild/moderate cases. PPIs: Long-term or severe cases; prescribe before meals for maximum effectiveness. Tailor therapy duration (e.g., 8 weeks for GERD, lifelong for Zollinger- Ellison syndrome). Always consider tapering to avoid rebound acid hypersecretion. Practice Questions 1. A 45-year-old man presents with occasional heartburn, especially after large meals. He has no history of esophageal injury or ulcer. Which medication would you prescribe? Answer: Famotidine 20 mg once or twice daily as needed. Explanation: Since the patient has mild and occasional symptoms, an H2 blocker is appropriate due to its rapid onset and suitability for intermittent use. 2. A 60-year-old woman has been diagnosed with erosive esophagitis confirmed by endoscopy. What is the best treatment? Answer: Omeprazole 20-40 mg QD for 8 weeks. Explanation: PPIs are the first-line treatment for erosive esophagitis due to their superior acid suppression and ability to promote mucosal healing. 3. A 50-year-old man with a history of GERD takes famotidine but reports persistent symptoms that wake him up at night. What is the next step? Answer: Switch to a PPI, such as esomeprazole 20-40 mg QD before breakfast. Explanation: Persistent symptoms despite H2 blocker use suggest the need for stronger acid suppression provided by a PPI. 4. A patient with peptic ulcer disease caused by H. pylori is starting treatment. Which medication should be included? Answer: Pantoprazole 40 mg BID as part of triple therapy. Explanation: PPIs are essential in H. pylori eradication regimens to enhance antibiotic effectiveness and promote ulcer healing. 5. A 35-year-old man asks for advice on managing his nighttime GERD symptoms. He has already tried lifestyle modifications. Which option is best? Answer: Famotidine 20 mg QHS or as needed. Explanation: H2 blockers are effective for nocturnal acid suppression and may be sufficient for nighttime symptoms in mild GERD. Comparing Antacids Antacids Definition: Antacids are over-the-counter medications that neutralize gastric acid, providing symptomatic relief from heartburn and dyspepsia. They act by increasing the pH of stomach contents. Factors: o Onset of action: Rapid (minutes).  o Neutralizing capacity: Varies by formulation. o Side effects: Aluminum-based (constipation), magnesium-based (diarrhea). Types of Antacids 1. Sodium Bicarbonate a. Mechanism: Reacts with gastric acid to produce carbon dioxide and sodium chloride, rapidly increasing gastric pH. b. Advantages: Quick onset of action. c. Disadvantages: i. Short duration of action. ii. May cause bloating and belching due to CO2 release. iii. Systemic absorption may lead to alkalosis or sodium overload. d. Example: Alka-Seltzer. 2. Calcium Carbonate a. Mechanism: Neutralizes gastric acid, producing calcium chloride and CO2. b. Advantages: Long-acting compared to sodium bicarbonate; provides dietary calcium supplementation. c. Disadvantages: i. May cause constipation. ii. Potential for rebound acid hypersecretion with overuse. iii. Risk of hypercalcemia in chronic users. d. Example: Tums, Rolaids. 3. Magnesium Hydroxide a. Mechanism: Neutralizes gastric acid without producing CO2. b. Advantages: Rapid and effective acid neutralization. c. Disadvantages: i. May cause diarrhea (osmotic effect). ii. Caution in patients with renal impairment due to risk of hypermagnesemia. d. Example: Milk of Magnesia. 4. Aluminum Hydroxide a. Mechanism: Neutralizes gastric acid and may bind bile salts, offering some protection to the gastric mucosa. b. Advantages: Minimal systemic absorption. c. Disadvantages: i. May cause constipation. ii. Prolonged use may lead to hypophosphatemia due to phosphate binding. d. Example: Amphojel. 5. Combination Products a. Purpose: Combine magnesium (to offset constipation) and aluminum (to offset diarrhea) for balanced effects.  b. Example: Maalox, Mylanta. Comparison Table Feature Antacids PPIs H2 Blockers Mechanis Neutralize Block acid production at Block acid secretion at m existing acid proton pump H2 receptor Onset of Immediate Moderate (30 min - 1 Slow (hours to a day) Action (minutes) hour) Duration of Short (30 mins - Long (24-48 hours) Moderate (6-12 hours) Effect 2 hours) Occasional GERD, erosive esophagitis, Mild GERD, nocturnal Best Use heartburn PUD acid reflux Effectivene Symptomatic Most potent acid suppression Less potent than PPIs ss relief only Side Constipation/di Long-term risks (e.g., nutrient Rare, but tolerance can Effects arrhea deficiencies) develop Examples Tums, Maalox Omeprazole, Pantoprazole Famotidine, Ranitidine 3. Anti-diarrheals Anti-diarrheal medications are used to reduce the frequency and urgency of bowel movements, manage dehydration, and improve patient comfort in various diarrheal conditions. They are not a cure but offer symptomatic relief. Common Conditions Treated with Anti-Diarrheals 1. Acute Non-Infectious Diarrhea a. Caused by stress, medications, or dietary changes. b. Example: Loperamide (Imodium). 2. Chronic Diarrhea a. Conditions like irritable bowel syndrome with diarrhea (IBS-D) or functional diarrhea. b. Examples: Loperamide, Eluxadoline. 3. Traveler’s Diarrhea  a. Often caused by bacterial infection (e.g., E. coli). b. Anti-diarrheals like loperamide may be combined with antibiotics if needed. 4. Diarrhea from Inflammatory Bowel Disease (IBD) a. Used cautiously to reduce symptoms without exacerbating underlying inflammation. b. Example: Cholestyramine (bile acid binder for diarrhea caused by bile salt malabsorption). 5. Diarrhea from Short Bowel Syndrome or Malabsorption a. Example: Octreotide (reduces intestinal secretions). 6. Radiation- or Chemotherapy-Induced Diarrhea a. Managed with specific agents like loperamide or octreotide. Examples of Anti-Diarrheal Medications and Their Mechanisms 1. Opiate Receptor Agonists ▪ Mechanism: Activate mu-opioid receptors in the GI tract, slowing intestinal motility and allowing more time for water absorption. ▪ Examples: Loperamide (Imodium): Does not cross the blood-brain barrier; safe for most non-infectious diarrheas. Diphenoxylate/Atropine (Lomotil): Central and peripheral effects; atropine added to prevent abuse. ▪ Uses: Acute diarrhea, IBS-D. ▪ Adverse Effects: Constipation, abdominal cramps; avoid in infectious diarrhea (e.g., C. difficile) due to risk of toxic megacolon. 2. Bile Acid Binders ▪ Mechanism: Bind bile acids in the gut, reducing their diarrheal effect. ▪ Examples: Cholestyramine, Colestipol. ▪ Uses: Bile acid diarrhea (e.g., post-cholecystectomy, Crohn’s disease).  ▪ Adverse Effects: Bloating, constipation, interference with fat-soluble vitamin absorption. How Bile Acids Cause Diarrhea Bile acid diarrhea (BAD) occurs when an excess of bile acids reaches the colon, leading to increased water secretion and motility. This condition can result from excessive bile acid production, impaired reabsorption, or abnormal bile acid handling by the intestines. 3. Antisecretory Agents ▪ Mechanism: Reduce intestinal fluid secretion. ▪ Examples: Bismuth Subsalicylate (Pepto-Bismol): Antimicrobial and anti- inflammatory properties; useful for traveler’s diarrhea. Octreotide: Inhibits secretion of GI hormones, reducing diarrhea in conditions like carcinoid syndrome or short bowel syndrome. ▪ Adverse Effects: Bismuth: Black tongue and stool; avoid in salicylate allergy or children (Reye’s syndrome risk). Octreotide: Gallstones, bradycardia. 4. Mixed Mechanism Agents ▪ Examples: Eluxadoline (Viberzi). ▪ Mechanism: Acts on opioid receptors (mu and kappa agonist, delta antagonist) to reduce bowel motility. ▪ Uses: IBS-D. Irritable Bowel Syndrome with Diarrhea (IBS-D). o Adverse Effects: Abdominal pain, pancreatitis (caution in patients without a gallbladder) Clinical Pearls for Anti-Diarrheals Infectious Diarrhea: o Avoid opiate-based anti-diarrheals (e.g., loperamide, diphenoxylate) in suspected infectious or inflammatory diarrhea (e.g., C. difficile, shigella, salmonella). o Treat the underlying infection first. Traveler’s Diarrhea:  o Loperamide may be used short-term for symptom relief but should be combined with antibiotics if bacterial infection is confirmed. IBS-D: o Use loperamide for symptom relief or Eluxadoline for more targeted treatment. Chronic Conditions: o Long-term use of loperamide or bile acid binders may be necessary in chronic diarrhea due to malabsorption. Contraindications: o Avoid in children under 2 years old (risk of severe dehydration or toxic megacolon). o Avoid in cases of blood/mucus in stool, high fever, or suspicion of toxic megacolon. Patient Education: o Emphasize hydration and electrolyte replacement, especially in acute diarrhea. o Teach patients to recognize red-flag symptoms that require medical attention (e.g., severe abdominal pain, fever, or persistent diarrhea). PANCE Practice Case Questions: Anti-Diarrheals Case 1 A 45-year-old male presents with a 2-week history of diarrhea. He recently returned from a business trip to India. Stool cultures confirm enterotoxigenic E. coli as the causative agent. What is the most appropriate treatment? A. Loperamide only B. Azithromycin only C. Loperamide and Ciprofloxacin D. Diphenoxylate/Atropine only Answer: C. Loperamide and Ciprofloxacin Rationale: Loperamide provides symptomatic relief by reducing bowel movements, while ciprofloxacin treats the underlying bacterial cause. Azithromycin is an alternative if fluoroquinolone resistance is suspected. Case 2 A 34-year-old female with a history of IBS-D presents with frequent diarrhea and abdominal pain. She has tried loperamide without relief. What is the next step in her treatment? A. Cholestyramine B. Eluxadoline C. Octreotide D. Diphenoxylate/Atropine Answer: B. Eluxadoline Rationale: Eluxadoline is FDA-approved for IBS-D and provides targeted action on opioid receptors to reduce diarrhea and pain. It is superior to loperamide for IBS-D when symptoms persist. Case 3 A 50-year-old male with Crohn’s disease undergoes ileal resection and presents with chronic diarrhea. What medication is most appropriate? A. Loperamide B. Cholestyramine C. Octreotide D. Bismuth Subsalicylate Answer: B. Cholestyramine Rationale: Bile acid diarrhea is common after ileal resection, and cholestyramine binds bile acids to reduce their diarrheal effect. Case 4 A 38-year-old male with a history of carcinoid syndrome presents with severe diarrhea. What is the most appropriate treatment?  A. Loperamide B. Octreotide C. Eluxadoline D. Diphenoxylate/Atropine Answer: B. Octreotide Rationale: Octreotide reduces diarrhea in carcinoid syndrome by inhibiting GI hormone secretion, which contributes to the symptoms. Case 5 A 70-year-old male undergoing chemotherapy presents with severe diarrhea. Stool studies are negative for infection. Which medication is most appropriate? A. Loperamide B. Diphenoxylate/Atropine C. Cholestyramine D. Bismuth Subsalicylate Answer: A. Loperamide Rationale: Loperamide is first-line therapy for chemotherapy-induced diarrhea due to its effective reduction in stool frequency and urgency. Case 6 A 25-year-old female with a recent diagnosis of ulcerative colitis presents with mild diarrhea. What is the best treatment option? A. Loperamide B. Cholestyramine C. Eluxadoline D. Diphenoxylate/Atropine Answer: A. Loperamide Rationale: Loperamide can be used cautiously in inflammatory bowel disease for mild, non- infectious diarrhea. Care should be taken to monitor for toxic megacolon. Case 7 A 40-year-old male with no significant past medical history presents with acute diarrhea after a stressful event. He denies fever, abdominal pain, or blood in the stool. What is the most appropriate medication? A. Loperamide B. Bismuth Subsalicylate C. Eluxadoline D. Cholestyramine Answer: A. Loperamide Rationale: Loperamide is effective for acute, non-infectious diarrhea caused by stress and helps reduce stool frequency. Case 8 A 55-year-old female reports black stool after starting a medication for traveler’s diarrhea. What medication is likely responsible? A. Loperamide B. Bismuth Subsalicylate C. Eluxadoline D. Octreotide Answer: B. Bismuth Subsalicylate Rationale: Bismuth can cause black stool (and tongue), which is a harmless side effect but important to distinguish from gastrointestinal bleeding. Case 9 A 45-year-old male with a history of gallbladder removal presents with chronic diarrhea. What is the best treatment option? A. Loperamide B. Cholestyramine C. Eluxadoline D. Octreotide Answer: B. Cholestyramine Rationale: Post-cholecystectomy diarrhea is often bile acid-mediated, and cholestyramine effectively binds bile acids to alleviate symptoms. Case 10 A 32-year-old male with IBS-D who does not have a gallbladder starts Eluxadoline and reports worsening abdominal pain. What is the likely cause? A. Pancreatitis B. Constipation C. Toxic Megacolon D. Hepatotoxicity Answer: A. Pancreatitis Rationale: Eluxadoline increases the risk of pancreatitis, particularly in patients without a gallbladder. The medication should be discontinued, and pancreatitis treated immediately. What is Eluxadoline? Eluxadoline (brand name: Viberzi) is a prescription medication approved by the FDA for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. It works by targeting specific opioid receptors in the gastrointestinal (GI) tract to reduce bowel motility and alleviate diarrhea and abdominal pain. It is particularly indicated for patients who have not responded adequately to lifestyle changes or other first-line therapies, such as loperamide. What is Eluxadoline? Eluxadoline (brand name: Viberzi) is a prescription medication approved by the FDA for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. It works by targeting specific opioid receptors in the gastrointestinal (GI) tract to reduce bowel motility and alleviate diarrhea and abdominal pain. Mechanism of Action Eluxadoline has a mixed mechanism of action: Mu-opioid receptor agonist: Reduces GI motility, slowing the movement of stool through the intestines. Kappa-opioid receptor agonist: Provides additional effects on reducing motility and improving symptoms. Delta-opioid receptor antagonist: Reduces the risk of constipation and prevents hypermotility rebound. This combination of actions makes Eluxadoline particularly effective for managing IBS-D symptoms while minimizing some of the side effects associated with other opioid-based medications. Indications Primary Use: Treatment of IBS-D, characterized by: o Frequent, loose, or watery stools. o Abdominal pain or discomfort. It is particularly indicated for patients who have not responded adequately to lifestyle changes or other first-line therapies, such as loperamide. Dosing Typical Dosage: o 100 mg twice daily with food. o 75 mg twice daily for patients who: ▪ Do not have a gallbladder. ▪ Have mild or moderate liver impairment.  ▪ Are at risk for side effects. Contraindications Eluxadoline is contraindicated in: 1. Patients without a gallbladder: Increased risk of pancreatitis. 2. Severe liver impairment (Child-Pugh Class C): Risk of drug accumulation and toxicity. 3. Biliary duct obstruction, sphincter of Oddi dysfunction, or a history of pancreatitis. 4. Alcohol abuse or consumption of >3 alcoholic drinks/day: Higher risk of pancreatitis. 5. Severe constipation: Risk of exacerbation. What is Pancreatitis? Pancreatitis is inflammation of the pancreas, a gland located behind the stomach that plays a vital role in digestion and blood sugar regulation. It occurs when the digestive enzymes produced by the pancreas become activate Gallbladder removal alters the dynamics of bile and pancreatic enzyme flow, increasing the risk of pancreatitis in some individuals. Infectious disease: GI biome Start with a detailed patient history and symptom assessment: Key Symptoms: o GERD-like symptoms: Heartburn, regurgitation, chest discomfort. o Infectious indicators: Fever, chills, night sweats, odynophagia (painful swallowing), dysphagia, weight loss, or diarrhea. o Associated GI symptoms: Nausea, vomiting, bloating, diarrhea, abdominal pain. Risk Factors: o Immunocompromised state (e.g., HIV/AIDS, recent chemotherapy). o Use of medications like PPIs (which can disrupt the GI microbiome).  o Recent travel, exposure to contaminated food/water, or close contact with infected individuals. Empirical Treatment or Targeted Therapy Treat empirically if strong suspicion exists for an infection while awaiting confirmatory tests: o H. pylori: Triple therapy (PPI + Amoxicillin + Clarithromycin) or quadruple therapy. o Candida esophagitis: Oral fluconazole. o HSV esophagitis: Acyclovir or Valacyclovir. o CMV esophagitis: IV Ganciclovir, especially in immunosuppressed patients. Key Notes: 1. Hydration: Oral rehydration solutions (ORS) are critical in managing all types of diarrheal diseases to prevent dehydration. 2. Antibiotic Stewardship: Avoid antibiotics in cases where they might worsen outcomes (e.g., EHEC, mild viral gastroenteritis). 3. Prevention: a. Vaccinations (e.g., rotavirus, typhoid). b. Safe food handling and water sanitation. Common GI Pathogens and Therapies Pathogen Therapy Escherichia coli Hydration, severe cases: Azithromycin or Ciprofloxacin (ETEC) Clostridioides Stop offending antibiotic; Oral Vancomycin or Fidaxomicin difficile Norovirus Supportive care (hydration) Salmonella Supportive care, severe cases: Azithromycin or Ciprofloxacin (nontyphoidal) Shigella Hydration, severe cases: Azithromycin or Ciprofloxacin Campylobacter Supportive care, severe cases: Azithromycin jejuni  PPI + Amoxicillin + Clarithromycin (or Metronidazole if Helicobacter pylori penicillin allergy) Rotavirus Supportive care, prevention with Rotavirus vaccine Giardia lamblia Metronidazole, Tinidazole, or Nitazoxanide When to Refer Refer to a gastroenterologist if symptoms persist despite treatment or if diagnostic tests are inconclusive. Immunocompromised patients with significant esophageal or GI symptoms should be co-managed with an infectious disease specialist. 4. Anti-spasmodics What is an Antispasmodic? An antispasmodic is a type of medication used to relieve or prevent muscle spasms in the smooth muscles of the body, particularly those in the gastrointestinal (GI) tract, urinary system, or uterus. These drugs work by either directly relaxing smooth muscle or inhibiting the signals that cause muscle contraction. Common Conditions Treated with Anti-Spasmodics 1. Irritable Bowel Syndrome (IBS) a. Anti-spasmodics help relieve abdominal pain and cramping associated with IBS, particularly in IBS with diarrhea (IBS-D). b. Example: Dicyclomine, Hyoscyamine. 2. Functional Gastrointestinal Disorders a. Conditions like functional dyspepsia or non-cardiac chest pain caused by esophageal spasms can benefit from anti-spasmodics. 3. Biliary Colic a. Used to alleviate pain caused by spasms in the bile ducts, often seen in gallbladder disease. 4. Diverticular Disease a. Helps reduce pain caused by colonic spasms associated with diverticulitis or diverticulosis. 5. Postoperative Bowel Spasms a. Administered after abdominal or pelvic surgery to minimize spasms in the bowel or bladder. 6. Genitourinary Spasms a. Used for conditions like bladder spasms (e.g., overactive bladder, interstitial cystitis) or ureteral spasms associated with kidney stones. b. Example: Oxybutynin, a urinary anti-spasmodic. 7. Menstrual Cramps (Dysmenorrhea) a. Anti-spasmodics can relieve uterine muscle spasms. Types of Antispasmodics: Anticholinergic Agents  o Mechanism: Block acetylcholine at muscarinic receptors, reducing smooth muscle contractions. o Medications: ▪ Dicyclomine (Bentyl): AntiCh, commonly used for IBS. ▪ Hyoscyamine (Levsin): Broad GI applications, including cramping and spasms. Calcium Channel Blockers (Off-label) o Mechanism: Inhibit calcium influx, reducing smooth muscle contraction. o Example: Nifedipine (used off-label for esophageal spasms). Clinical Pearls Targeted Use: Anti-spasmodics are typically prescribed for symptom relief rather than long-term disease management. Caution: b. Anticholinergic effects (dry mouth, constipation, urinary retention) may limit use in elderly patients. c. Avoid in patients with conditions like glaucoma or severe ulcerative colitis due to risk of toxic megacolon. On-Demand Use: For conditions like IBS, anti-spasmodics can be taken as needed during symptomatic episodes. Key Example Prescriptions 1. Dicyclomine 20 mg QID (as needed) for abdominal cramping in IBS. 2. Hyoscyamine 0.125 mg sublingually PRN for GI or urinary spasms. Cholinergic vs. Anticholinergic: Key Differences Cholinergic and anticholinergic refer to the effects on the parasympathetic nervous system (PNS), which is a division of the autonomic nervous system. These terms relate to the neurotransmitter acetylcholine (ACh) and its receptors. 1. Cholinergic Cholinergic refers to substances or actions that mimic or enhance the effects of acetylcholine by stimulating its receptors. How It Works Receptors Activated: o Muscarinic receptors (in smooth muscle, heart, glands): Mediates parasympathetic functions. o Nicotinic receptors (in skeletal muscle and autonomic ganglia): Affects muscle contraction and autonomic signaling. Functions: Rest-and-digest activities of the parasympathetic nervous system. o Slows heart rate. o Increases glandular secretions (saliva, sweat, mucus). o Enhances gastrointestinal motility. o Constricts pupils (miosis). Examples of Cholinergic Drugs Bethanechol: Increases bladder contraction and GI motility. Pilocarpine: Treats glaucoma by increasing aqueous humor outflow. Acetylcholinesterase inhibitors (e.g., Donepezil, Neostigmine): Prevent breakdown of ACh, enhancing its effects. Clinical Uses Urinary retention.  Myasthenia gravis (increased muscle strength). Glaucoma. Alzheimer’s disease. Side Effects (Excess Cholinergic Activity) SLUDGE: Salivation, Lacrimation, Urination, Diarrhea, GI upset, Emesis. Bradycardia, hypotension. Bronchospasm. 2. Anticholinergic Anticholinergic refers to substances or actions that inhibit the effects of acetylcholine by blocking its receptors. How It Works Receptors Blocked: o Muscarinic receptors: Blocks parasympathetic effects. o Nicotinic receptors are usually unaffected at therapeutic doses. Functions: Opposes rest-and-digest activities. o Increases heart rate. o Reduces secretions (dry mouth, dry skin). o Decreases gastrointestinal motility. o Dilates pupils (mydriasis). Examples of Anticholinergic Drugs Atropine: Increases heart rate in bradycardia; dilates pupils. Ipratropium/Tiotropium: Bronchodilators for COPD. Oxybutynin: Treats overactive bladder by reducing bladder contractions. Scopolamine: Prevents motion sickness. Diphenhydramine (antihistamine with anticholinergic properties). Clinical Uses Overactive bladder.  Asthma/COPD (reducing bronchoconstriction). Motion sickness. Irritable bowel syndrome (IBS) to reduce spasms. Side Effects (Anticholinergic Toxicity) Dry as a bone (dry mouth, dry skin). Blind as a bat (blurred vision, mydriasis). Red as a beet (flushed skin). Hot as a hare (hyperthermia). Mad as a hatter (confusion, delirium). Bowel and bladder lose their tone (constipation, urinary retention). Tachycardia. Clinical Scenarios Cholinergic Drugs: Treat conditions where parasympathetic activity is low or desired (e.g., urinary retention, glaucoma, myasthenia gravis). Anticholinergic Drugs: Treat conditions where parasympathetic activity is excessive or needs suppression (e.g., asthma, motion sickness, overactive bladder). 5. Promotility Agents Promotility agents are often used to treat conditions where GI motility is slowed or impaired. Examples: Metoclopramide, Erythromycin. Mechanism of Action: o Metoclopramide: Dopamine (D2) receptor antagonist; enhances acetylcholine release to increase gastric emptying. o Erythromycin: A macrolide antibiotic, mimics motilin to promote gastric motility. Adverse Effects: Metoclopramide may cause tardive dyskinesia with prolonged use. Erythromycin: Tachyphylaxis (reduced effectiveness over time), abdominal cramping, diarrhea. Short-Term Use: Prokinetics like metoclopramide are typically prescribed for short durations to minimize adverse effects. Dopamine's Normal Effect: Dopamine acts as an inhibitory neurotransmitter in the enteric nervous system. Activation of D2 dopamine receptors on cholinergic neurons suppresses acetylcholine release. o This reduces GI motility by decreasing the excitatory signals needed for peristalsis and coordinated muscle contractions. Dopamine Receptor Antagonism: Dopamine receptor antagonists block D2 receptors on presynaptic cholinergic neurons. This removes dopamine's inhibitory effect, leading to: o Increased acetylcholine release from cholinergic neurons. o Enhanced stimulation of muscarinic receptors on smooth muscle cells in the GI tract. The result is increased peristalsis, improved gastric emptying, and enhanced GI motility. Common Uses of Promotility/Prokinetic Medications 1. Gastroesophageal Reflux Disease (GERD) a. Prokinetics improve the tone and coordination of the lower esophageal sphincter (LES), reducing acid reflux. b. Example: Metoclopramide. 2. Gastroparesis a. A condition characterized by delayed gastric emptying, often seen in diabetes or after surgery. b. Prokinetics stimulate gastric motility to improve symptoms like nausea, vomiting, and bloating. c. Example: Metoclopramide, Erythromycin. 3. Functional Dyspepsia a. Non-ulcer-related upper abdominal discomfort often linked to sluggish gastric motility. b. Prokinetics can provide relief by improving gastric emptying. c. Example: Domperidone (not FDA-approved in the U.S.). 4. Ileus (Postoperative or Paralytic) a. Used to stimulate bowel motility in cases of decreased peristalsis following surgery or other causes. b. Example: Metoclopramide. 5. Irritable Bowel Syndrome (IBS) with Constipation (IBS-C) a. Prokinetics like prucalopride (a serotonin agonist) help improve colonic motility to relieve constipation. 6. Small Bowel Bacterial Overgrowth (SIBO) a. Prokinetics may assist in clearing bacteria from the small intestine by enhancing intestinal motility.