UPPER GI

Introduction to the GI Section

This section focuses on the upper gastrointestinal (GI) tract, primarily examining Peptic Ulcer Disease (PUD) and Gastroesophageal Reflux Disease (GERD). Understanding these conditions involves recognizing the balance between protective and aggressive factors within the stomach and duodenum, and how different pharmacologic classes work to restore that balance.

Peptic Ulcer Disease (PUD)

Definition

• An ulcer is a break in the mucosal lining that extends through the muscularis mucosa.

• Erosions are more superficial and limited to the mucosal layer.

• Ulcers occur when aggressive factors (acid, pepsin) overpower defensive mechanisms (mucus, bicarbonate, prostaglandins, blood flow).

Common Sites

• Duodenal ulcers (most common)

• Gastric ulcers (stomach wall)

• Less commonly: esophagus or lower small intestine (in Zollinger-Ellison syndrome)

Epidemiology

• ~25 million Americans affected; lifetime prevalence of 10–12%.

Main Causes

1. Helicobacter pylori infection

   • A gram-negative, spiral-shaped bacterium that thrives in the stomach’s mucus layer.

   • Produces urease, converting urea to ammonia, neutralizing surrounding acid.

   • Causes chronic gastritis, damages the mucosa, and disrupts local defenses.

2. NSAID use

   • Inhibits COX-1, reducing prostaglandin synthesis, which is essential for mucus, bicarbonate secretion, and mucosal blood flow.

   • Without prostaglandins, mucosal defenses weaken, and ulcers form.

3. Stress-related mucosal damage (SRMD)

   • Triggered by severe physiologic stress (ICU stay, sepsis, burns, mechanical ventilation).

   • Decreased blood flow and mucosal ischemia impair the barrier and healing.

Mucosal Protection

Defensive Factors

1. Mucus secretion: Provides a physical barrier.

2. Bicarbonate secretion: Neutralizes acid at the epithelial surface.

3. Microcirculation: Maintains tissue oxygenation and removes acid that penetrates.

Prostaglandin Role

• Stimulates mucus and bicarbonate secretion.

• Promotes vasodilation to sustain mucosal blood flow.

• NSAID-induced prostaglandin inhibition is therefore a key ulcer mechanism.

Helicobacter pylori

Characteristics

• Gram-negative, acid-labile (cannot survive freely in stomach acid).

• Resides between the mucus layer and epithelial cells.

• Spread via fecal-oral or oral-oral transmission.

Clinical Significance

• Present in up to 90% of duodenal ulcers and 75% of gastric ulcers.

• Also linked to chronic gastritis and gastric adenocarcinoma.

Diagnosis

• Urea breath test, stool antigen test, or biopsy urease test (CLO test).

H. pylori Eradication Therapy

First-Line: Optimized Bismuth Quadruple Therapy

• Bismuth subsalicylate/subcitrate

• Metronidazole

• Tetracycline

• PPI (e.g., omeprazole)
  → Duration: 14 days.

Examples

• Helidac® + PPI

• Pylera® + PPI

Alternative Regimens

• Talicia®: Rifabutin + Amoxicillin + Omeprazole

• Voquenza DualPak®: Vonoprazan (potassium-competitive acid blocker) + Amoxicillin

Goal: Eradicate infection to prevent recurrence, not just heal ulcers.

NSAID-Induced Ulcers

• NSAIDs inhibit COX enzymes, reducing prostaglandin levels.

• Leads to less mucus and bicarbonate, decreased blood flow, and epithelial vulnerability.

• Prevention: use of PPIs or misoprostol in high-risk patients.

Gastroesophageal Reflux Disease (GERD)

Definition

• Backflow of gastric contents into the esophagus, causing symptoms or mucosal injury.

Epidemiology

• Most common GI disorder in adults.

• ~10% of adults experience daily heartburn; 44% at least monthly.

• Chronic, relapsing, often requiring lifelong management.

Pathophysiology

• Lower Esophageal Sphincter (LES) dysfunction → reflux.

• Increased intra-abdominal pressure (obesity, large meals, tight clothing).

• Hiatal hernia can exacerbate reflux by disrupting LES position.

Symptoms

• Heartburn (retrosternal burning pain)

• Regurgitation (acidic or sour fluid)

• Belching, bloating, nausea

• Early satiety

Untreated GERD may progress to esophagitis, strictures, or Barrett’s esophagus (a precancerous condition).

Lifestyle Modifications

1. Weight loss

2. Small, low-fat meals

3. Avoid trigger foods – citrus, tomato, chocolate, caffeine, alcohol.

4. Avoid lying down for 2–3 hours after meals

5. Elevate head of bed

6. Quit smoking

7. Avoid tight waistbands or belts

Pharmacologic Treatment Overview

1. Antacids

• Mechanism: Neutralize gastric acid directly.

• Onset: Rapid; Duration: 30–180 min.

• Use: Immediate, short-term relief.

Combination Products:

• Mylanta®, Maalox® – Aluminum + Magnesium (balance bowel effects)

• Rolaids® – Calcium + Magnesium

Patient Education:

• Take 1 and 3 hours after meals and at bedtime.

• Space 1–2 hours apart from other medications (prevents binding).

• Shake liquids, refrigerate for taste, chew tablets completely.

• Avoid milk or vitamin D with calcium antacids.

2. Alginic Acid (Gaviscon®)

• Forms foam barrier floating on gastric contents.

• Useful for upright reflux, but ineffective for nighttime/supine reflux.

• Often combined with aluminum and magnesium antacids.

3. Histamine-2 Receptor Antagonists (H2RAs)

• Mechanism: Block H₂ receptors on parietal cells → ↓ acid secretion by 50–70%.

• Examples:

  • Famotidine (Pepcid®, Zantac 360®)

  • Cimetidine (Tagamet®) – Rarely used (causes gynecomastia, impotence).

  • Nizatidine (Axid®)

Use: Mild-to-moderate GERD, PUD adjunct therapy.
Tolerance: May develop after prolonged use.

4. Proton Pump Inhibitors (PPIs)

• Mechanism: Irreversibly inhibit H⁺/K⁺ ATPase pump → 80–95% acid reduction.

• Examples: Omeprazole (Prilosec®), Lansoprazole (Prevacid®), Esomeprazole (Nexium®).

• Administration: Take 20–30 min before first major meal.

• Long-term risks:

  • Pneumonia (bacterial overgrowth + aspiration)

  • Osteoporosis (fracture risk; consider Ca/Vit D supplements)

Vonoprazan (Voquenza®):

• Newer PPI, acid-stable, doesn’t need meal timing, fast-acting.

• Expensive but effective alternative; reduces acid by 85–90%.

5. Sucralfate (Carafate®)

• Forms protective coating over ulcers (requires pH <4).

• Minimal absorption; constipation possible.

• Used for mucosal injuries (e.g., chemo-induced or radiation).

• Caution in renal failure (aluminum content).

6. Simethicone (Gas-X®, Mylicon®)

• Defoaming agent – breaks down large gas bubbles → relieves bloating and pressure.

• Locally acting, safe for all ages, including infants.

• Often added to antacid combinations (e.g., Mylanta Gas®).

Summary: Upper GI Pharmacologic Strategies

Nausea and Vomiting (N/V)

Overview

Nausea → the subjective feeling of needing to vomit.
Vomiting (emesis) → the forceful expulsion of stomach contents through the mouth.

Together, these are protective reflexes meant to rid the body of harmful substances, but they can become problematic when excessive or chronic.

Clinical Importance

Excessive or prolonged vomiting can cause:

• Dehydration

• Electrolyte loss (especially sodium, potassium, and chloride)

• Metabolic alkalosis (loss of gastric acid)

• Malnutrition

• Esophageal damage or Mallory-Weiss tears (from repeated retching)

Common Causes

Nausea and vomiting are symptoms, not diseases, and may result from:

• Gastrointestinal causes: infections, obstruction, gastritis, ulcer, GERD

• Cardiovascular causes: myocardial infarction, heart failure

• Neurologic causes: increased intracranial pressure, migraines, vestibular disorders

• Metabolic causes: uremia, diabetic ketoacidosis, pregnancy (morning sickness)

• Therapy-related: chemotherapy, radiation, anesthesia, opioids, or withdrawal

• Psychogenic causes: anxiety, stress, sight/smell triggers

The Emetic (Vomiting) Center

• Located in the medulla oblongata of the brainstem.

• Coordinates input from multiple sources that trigger nausea and vomiting:

  1. Chemoreceptor Trigger Zone (CTZ) – detects toxins/drugs in blood and CSF.

     • Stimulated by chemotherapy agents, opioids, digoxin, and metabolic toxins.

  2. Vestibular system – motion sickness; rich in muscarinic and histamine (H1) receptors.

  3. Cerebral cortex – sensory or emotional input (fear, pain, smell, sight).

  4. GI tract and vagus nerve – irritation or distention signals to the emetic center.

  5. Higher centers – anticipation or memory of nausea (as in chemotherapy).

These pathways use several neurotransmitters:

• Dopamine (D2)

• Serotonin (5-HT3)

• Histamine (H1)

• Acetylcholine (muscarinic)

• Neurokinin-1 (substance P)

Understanding these receptors is crucial because antiemetic drugs target them selectively.

Major Antiemetic Drug Classes

1. Anticholinergic Agents

Examples:

• Scopolamine (Transderm-Scop®) – transdermal patch behind ear

• Meclizine (Antivert®)

• Dimenhydrinate (Dramamine®)

Mechanism:

• Block muscarinic (M1) receptors in the vestibular system and vomiting center.

Best for:

• Motion sickness

• Vertigo

• Mild nausea (e.g., from travel or dizziness)

Adverse Effects (anticholinergic):

• Drowsiness, dry mouth, blurred vision, constipation, urinary retention

• Caution in elderly or glaucoma patients due to CNS and ocular effects.

2. Serotonin (5-HT3) Receptor Antagonists

Examples:

• Ondansetron (Zofran®)

• Granisetron (Kytril®)

• Dolasetron (Anzemet®)

• Palonosetron (Aloxi®) – longer duration (up to 5–7 days)

Mechanism:

• Block 5-HT3 receptors in the GI tract and CTZ.

• Prevent serotonin released from the small intestine (especially by chemotherapy) from triggering nausea and vomiting.

Best for:

• Chemotherapy-induced nausea and vomiting (CINV)

• Post-operative nausea/vomiting (PONV)

• Radiation therapy–induced nausea

Adverse Effects:

• Headache

• Constipation or diarrhea

• QT interval prolongation (rare; caution with cardiac patients)

3. Dopamine (D2) Receptor Antagonists

Examples:

• Promethazine (Phenergan®) – also blocks histamine (H1) receptors → strong sedation

• Metoclopramide (Reglan®) – also enhances gastric motility (prokinetic)

Mechanism:

• Block dopamine receptors in the CTZ.

• Metoclopramide also increases GI motility and accelerates gastric emptying—useful for diabetic gastroparesis.

Best for:

• General-purpose antiemetic (post-op, migraine, or drug-induced)

• Gastroparesis (metoclopramide)

Adverse Effects:

• Drowsiness, confusion (especially in elderly)

4. Cannabinoids

Examples:

• Dronabinol (Marinol®)

• Nabilone (Cesamet®)

Mechanism:

• Activate CB1 receptors in the brain and GI tract, reducing emetic signaling and promoting appetite.

Best for:

• Refractory nausea/vomiting not relieved by standard agents

• Chemotherapy-related nausea

• Appetite stimulation in AIDS or cancer cachexia

Adverse Effects:

• Sedation, dizziness, euphoria, ataxia, dysphoria (unpleasant mood changes)

• May impair short-term memory and coordination

5. Corticosteroids

Examples:

• Dexamethasone (Decadron®)

• Methylprednisolone (Solu-Medrol®)

Mechanism:

• Unclear; possibly block inflammation and prostaglandin-mediated signals in the vomiting center.

Best for:

• Chemotherapy-induced or post-surgical nausea

• Often used in combination with serotonin or neurokinin antagonists.

Adverse Effects:

• Generally mild with short-term use.

• Long-term use → hyperglycemia, immunosuppression, insomnia, and mood changes.

6. Neurokinin-1 (NK1) Receptor Antagonists

Example:

• Aprepitant (Emend®)

Mechanism:

• Blocks substance P from binding to NK1 receptors in the brain, a key pathway in delayed-phase chemotherapy-induced nausea.

Best for:

• Chemotherapy-induced or postoperative nausea/vomiting

• Often combined with a 5-HT3 antagonist and dexamethasone for maximal efficacy.

Adverse Effects:

• Generally well tolerated

• Possible fatigue or hiccups

Combination Therapy

• For chemotherapy:
  5-HT3 antagonist + corticosteroid + NK1 antagonist
  → synergistic effect covering both acute and delayed phases of emesis.

• For motion sickness:
  Anticholinergic + antihistamine combinations may be used short-term.

Summary Table: Antiemetic Overview

Key Takeaways

• Identify source and neurotransmitter pathway of nausea before selecting therapy.

• Combine agents from different classes for refractory cases.

• Watch for drug interactions and CNS depression when combining sedating agents.

• Treat the underlying cause when possible (e.g., infection, obstruction, medication side effect).