Gastro-oesophageal Reflux Disease (GORD) 

Pathophysiology of GORD

• LES Incompetence
• Impaired Oesophageal Mucosal Resistance
• Decreased Oesophageal Clearance

TLESR Criteria (on Manometry)

• Swallow-induced LES pressure declines >3mmHg to <2mmHg above intragastric pressure for >5s post-swallow
  OR
• LES relaxations >10s

1. Proton Pump Inhibitors (PPIs)

• Pantoprazole, Omeprazole, Lansoprazole, Rabeprazole, Esomeprazole
• Best for patients with overlapping dyspepsia and gastro-oesophageal reflux disease (GORD).
• Long-term use should be monitored due to potential side effects (e.g., osteoporosis, microbiome changes).

2. H2 Receptor Antagonists (H2As)

• Famotidine, Cimetidine, Ranitidine (withdrawn in some markets due to safety concerns), Nizatidine

3. Lower Oesophageal Sphincter (LES) Relaxants

• Nitrates
• Calcium Channel Blockers (Nifedipine, Amlodipine)

4. GABA(B) Agonist: Baclofen

• Short-term trials suggest reduces transient LES relaxations (TLESRs), increases LOS pressure, reduces reflux episodes, and improves reflux-related symptoms.
• Also increases gastric emptying.
• Side effects: Drowsiness, dizziness—monitor while on therapy.

5. Neuromodulation

• Tricyclic Antidepressants (TCAs): Amitriptyline, Nortriptyline (Nortriptyline preferred if drowsiness is a concern).

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Prokinetics: An Overview

Prokinetic agents are medications designed to enhance gastrointestinal motility by accelerating gastric emptying. However, the relationship between their physiological effects and symptom relief remains complex. This document explores the challenges and considerations in prokinetic therapy, available treatment options, and the evolving approach to managing motility disorders.

Symptom Response vs. Gastric Emptying

• There is limited correlation between the acceleration of gastric emptying and symptom relief, suggesting that factors beyond measurable gastric motility play a role in patient outcomes.

Multiple Contributing Factors

• Symptoms in conditions like gastroparesis, functional dyspepsia, and irritable bowel syndrome (IBS) are influenced by complex mechanisms beyond gastric emptying alone.

Safety Concerns with Prokinetics

Effective but non-selective agents have been abandoned due to intolerable side effects:

• Cholinergics: Caused significant bladder spasms.
• Cisapride: Linked to cardiac arrhythmias (Torsades de Pointes, ventricular tachycardia), leading to its withdrawal.
• Tegaserod: Raised concerns regarding cardiac safety.

Drug Development Constraints

• A strict "safety-first" policy for non-life-threatening conditions limits the development of new drugs for debilitating motility disorders such as gastroparesis and intestinal pseudo-obstruction.

Potential Benefits of Multi-Targeted ("Dirty") Drugs

While highly selective agents are preferred to minimize adverse effects, some multi-target drugs may provide enhanced symptom relief:

• 5-HT4 agonist & 5-HT3 antagonist combinations: May be beneficial in IBS.
• Linaclotide: Primarily a pro-secretory agent, but also has unexpected pain-relieving effects in constipation-predominant IBS.
• Prucalopride: A highly selective 5-HT4 agonist with potential neuroprotective effects relevant to enteric neuropathic disorders.

QT Prolongation Risk Across Drug Classes

Many commonly used medications can prolong the QT interval, necessitating careful patient monitoring. These include:

• Antihistamines: Diphenhydramine
• Antidepressants: Amitriptyline, citalopram, mirtazapine
• Antipsychotics: Haloperidol, quetiapine
• Macrolide antibiotics: Erythromycin, azithromycin

Comprehensive Management Approach

Given the multifactorial nature of motility disorders, an integrative approach addressing nausea, pain, gastric function, and psychological health may improve outcomes.

Differential Diagnoses

Conditions that may mimic gastroparesis or other motility disorders include:

• Peptic ulcer disease, gastric cancer, coeliac disease, abdominal angina.
• Anastomotic ulcers, internal herniation, gallbladder disease (for early dumping syndrome).
• Insulinoma or surreptitious use of glucose-lowering medications (for late dumping syndrome).

Prokinetic Agents and Related Therapies

Cholinergic Agents

• Neostigmine (muscarinic M2 agonist) – Used in Ogilvie’s syndrome.
• Pyridostigmine – Used for pseudo-obstruction.

Dopamine Antagonists

• Metoclopramide (DA, 5-HT3/4 antagonist, mild anticholinesterase activity) – Side effects: fatigue, sleepiness, depression, akathisia, anxiety, dyskinesia.
• Domperidone (DA2 antagonist) – 10–20 mg QID; requires cardiac monitoring due to potential QT prolongation.

Serotonin Agonists

• Mosapride (selective 5-HT4/3) – Minimal QT prolongation risk, common side effects include mild GI disturbances.
• Prucalopride (highly selective 5-HT4 agonist) – Greater efficacy with minimal cardiac risks.
• Mirtazapine (tetracyclic antidepressant, 5-HT1A/2A/3 antagonist) – May contribute to fundus relaxation, antiemetic, and anxiolytic effects.

Macrolide Antibiotics (Motilin Receptor Agonists)

• Erythromycin (IV: 3 mg/kg every 8 hours; Oral: 250 mg TID) – Risk of tachyphylaxis; use at lower doses may prolong efficacy.
• Azithromycin – Similar efficacy with less QT prolongation.

Other Treatments

• Botulinum Toxin (Botox®) – Occasionally used for pyloric dysfunction.
• Complementary Therapies – Ginger, peppermint, Iberogast, melatonin, and capsaicin may offer symptomatic relief in functional dyspepsia.
• 5-HT3 Antagonists – Ondansetron (4–8 mg TID PO, IV, PR), granisetron.
• Phenothiazines – Prochlorperazine (Stemetil®) for nausea.
• Antihistamines – Cyclizine, diphenhydramine, and cyproheptadine (Periactin™).
• Neurokinin-1 Receptor Antagonists – Aprepitant (125 mg daily).
• Anticholinergics – Scopolamine patch.
• Benzodiazepines – Lorazepam (used in chemotherapy-related anticipatory nausea).

Conclusion

While prokinetic therapy plays a key role in managing gastrointestinal motility disorders, challenges remain due to limited symptom correlation, safety concerns, and regulatory constraints. A balanced approach, integrating pharmacologic and non-pharmacologic strategies, is essential for optimizing patient outcomes. Future research may identify novel agents that offer enhanced efficacy with improved safety profiles.

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Abdominal/Chest Pain Modulation

1. Psychosocial Therapies
   • Strongly indicated for severe pain, impaired quality of life (QOL), and mood/anxiety disorders.
   • Options include:
     • Cognitive Behavioral Therapy (CBT): Proven to help in functional gastrointestinal disorders (FGIDs).
     • Gut-Directed Hypnotherapy: Effective for visceral hypersensitivity and functional dyspepsia (FD).
     • Biofeedback: Useful for stress-related GI symptoms.
     • Social Support: Social workers may assist in workplace/home/school adjustments.
2. Neuromodulators (for Visceral Hypersensitivity & Functional Dyspepsia)
   • Tricyclic Antidepressants (TCAs): Amitriptyline, nortriptyline (helpful even at low doses).
   • Mirtazapine: Particularly useful for nausea and weight loss.
   • Gabapentinoids (Gabapentin, Pregabalin): Reduce visceral pain sensitivity, may be beneficial in patients with FD and early satiety.
3. Serotonin Antagonist
   • Cyproheptadine: Particularly beneficial for postprandial distress syndrome (PDS) subtype, especially in younger patients with early satiety.
4. Proton Pump Inhibitors (PPIs)
   • Pantoprazole, Omeprazole, Lansoprazole, Rabeprazole, Esomeprazole
   • Best for patients with overlapping dyspepsia and gastro-oesophageal reflux disease (GERD).
   • Long-term use should be monitored due to potential side effects (e.g., osteoporosis, microbiome changes)

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Management of Abdominal Bloating

1. Antifoaming Agents & Surfactants

• Simethicone: Alters gas bubble elasticity, facilitating gas passage.
• Activated Charcoal: May help reduce gas formation and odour.

2. Prokinetics

• Erythromycin (low-dose): Motilin agonist, accelerates gastric emptying.
• Metoclopramide: Dopamine antagonist, enhances gastric motility (long-term use may cause tardive dyskinesia).

3. Antibiotics for Suspected Bacterial Overgrowth

• Rifaximin: Poorly absorbed, highly effective against both aerobic and anaerobic bacteria in small intestinal bacterial overgrowth (SIBO).
• Metronidazole (Flagyl®) and Trimethoprim/Sulfamethoxazole (Bactrim®): Alternative options if Rifaximin is unavailable or ineffective.

4. Probiotics

• Bifidobacterium infantis (35624 strain):
  • Demonstrated positive effects in randomized controlled trials (RCTs).
  • Reduces intestinal inflammation and improves symptoms of pain, bloating, and bowel movement difficulties compared to placebo.
• Other probiotic strains:
  • Lactobacillus GG and Saccharomyces boulardii may also be beneficial in select cases.

5. Digestive Enzymes

• Lactase: Useful for lactose intolerance.
• Alpha-galactosidase (Beano): Helps break down fermentable carbohydrates to reduce bloating.
• Pancreatic enzyme supplements: Beneficial in pancreatic insufficiency to aid digestion.

6. Aperients (Laxatives) for Constipation-Related Bloating

A. Laxatives Less Likely to Cause Bloating

• Osmotic Laxative: Polyethylene Glycol (PEG/Miralax) → Softens stools with minimal bloating.
• Bulk-Forming Laxative: Methylcellulose (Citrucel) → Non-fermentable, less likely to cause gas.
• Stimulant Laxative: Senna (low dose) → Effective for short-term relief of constipation-related bloating.
• Natural Option: Kiwi Fruit → Increases bowel movement frequency with low bloating risk.

B. Laxatives That May Worsen Bloating

• Lactulose & Magnesium Hydroxide: Can cause gas and bloating due to fermentation.
• Psyllium (Metamucil): Fermentable fiber, can increase bloating if not taken with sufficient water.
• Prunes (Dried Plums): Contain sorbitol and fructans, which may cause bloating in some individuals.

7. Dietary Approaches

• Low FODMAP Diet:
  • Well-established for reducing bloating and IBS symptoms.
• Elemental Diet (for severe SIBO cases):
  • Reduces fermentation and supports gut healing.

8. Herbal & Alternative Therapies

• Peppermint Oil (Enteric-Coated):
  • Works as an antispasmodic, reduces bloating.
  • Clinical trials show benefits in IBS and functional dyspepsia.
• Iberogast (Combination of Herbal Extracts):
  • Includes chamomile, peppermint, licorice root.
  • Helps functional dyspepsia, bloating, and motility disorders.
• Ginger Extract:
  • Stimulates gastric emptying, reduces nausea and bloating.

 

Diet:

gastroparesis (Postprandial fullness, early satiety, bloating, abdominal distension, nausea, and vomiting, abdominal pain, and dysphagia): "fork mashable"foods (low particle size diet), Low fat, low fiber foods small frequent meals

anti-dumping diet if rapid GE (

Early dumping syndrome (within 1 h after meal ingestion Gastrointestinal symptoms: Abdominal pain, epigastric fullness, diarrhea, nausea, vomiting, borborygmi, and bloating Vasomotor symptoms: desire to lie down, palpitations and tachycardia, fatigue, faintness, syncope, perspiration, headache, light-headedness, hypotension, flushing, and pallor

Late dumping syndrome (1–3 h after meal ingestion) Neuroglycopenia: fatigue, weakness, confusion, hunger and syncope Autonomic reactivity: perspiration, palpitations, tremor and irritability

(20% of patients suffer from symptoms of dumping syndrome after vagotomy and pyloroplasty,  40% after Roux-en-Y bypass and sleeve gastrectomy, and peak at 50% after esophagectomy): Eat small, frequent meals at least 6 times a day; Lie down as soon as you finish eating. Avoid: simple sugars such as sweets,high sugar soft drinks, cakes, and cookies. Avoid foods that are very hot or very cold. . These can trigger dumping syndrome symptoms. Do not drink liquids with your meal. Instead, drink liquids at least a 30 minutes to an hour after eating solid food. Encourage high-fibre, high-protein food

Prunes. Dried plums (prunes) not only contain fiber but also sorbitol and fructans, non-absorbable carbohydrates that, when fermented by colonic bacteria, create an osmotic load that can dramatically alter stool frequency and consistency. In an 8-week single-blind, randomized study with 40 constipated subjects, the number of CSBMs per week and stool consistency scores improved significantly (P < 0.05) with prunes when compared to psyllium. Straining and global constipation symptoms did not differ significantly between treatments.⁸⁷

Kiwi. In a recent study from Asia, 41 IBS-C patients and 16 healthy adults consumed 2 Hayward green kiwifruits per day for 4 weeks. Another 13 IBS-C patients served as controls. IBS-C patients that consumed kiwi fruit had a significantly faster colonic transit time than controls (P = 0.026). The IBS-C kiwifruit group also reported increases in defecation frequency and improvements in bowel function

Safe prescription of drugs which prolong the QTc interval